Letram

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LЕTRAM (LETRAM)

Composition:

Active substance: levetiracetam;

1 tablet contains 250 mg, 500 mg, or 1000 mg of levetiracetam;

Excipients: maize starch, sodium croscarmellose, povidone, colloidal anhydrous silicon dioxide, talc, magnesium stearate;

Film coating:

tablets 250 mg: Opadry II Blue 85F20694 [polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, indigo carmine (E 132)];

tablets 500 mg: Opadry II Yellow 85F32004 [polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, iron oxide yellow (E 172)];

tablets 1000 mg: Opadry II White 85F18422 [polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc].

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets 250 mg: blue-colored, oblong-shaped, film-coated tablets with a score line, marked with "Н" on one side and "87" on the other;

Tablets 500 mg: yellow-colored, oblong-shaped, film-coated tablets with a score line, marked with "Н" on one side and "88" on the other;

Tablets 1000 mg: white-colored, oblong-shaped, film-coated tablets with a score line, marked with "Н" on one side and "91" on the other.

Pharmacotherapeutic group. Antiepileptic drugs. Levetiracetam.

ATC code N03A X14.

Pharmacological properties.

Pharmacodynamics.

The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine-acetamide) whose chemical structure differs from that of known antiepileptic drugs.

Mechanism of action

The mechanism of action of levetiracetam is not fully understood, but it has been established that it differs from the mechanisms of action of known antiepileptic agents. Based on in vitro and in vivo studies, levetiracetam is believed not to alter basic neuronal cell characteristics or normal neurotransmission.

In vitro studies have shown that levetiracetam affects intraneuronal Ca2+ levels by partially inhibiting Ca2+ 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 rodent brain tissue. This binding site is synaptic vesicle protein 2A (SV2A), which is involved in vesicle fusion and neurotransmitter release. Levetiracetam and its structural analogs exhibit a rank order of affinity for binding to synaptic vesicle protein 2A that correlates with their anticonvulsant activity in the audiogenic seizure model in mice. These findings suggest that the interaction between levetiracetam and synaptic vesicle protein 2A contributes to the antiepileptic effect of the drug.

Pharmacodynamic effects

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

In humans, the efficacy of the drug in both partial and generalized forms of epilepsy (epileptiform discharges / photoparoxysmal response) confirms the broad pharmacological profile of levetiracetam.

Pharmacokinetics.

Levetiracetam is a highly soluble and permeable compound. Its pharmacokinetic profile is linear and characterized by low inter- and intrasubject variability. No changes in clearance are observed after repeated administration. There is no evidence of clinically relevant differences related to gender, race, or circadian rhythm. The pharmacokinetic profile was similar in healthy volunteers and patients with epilepsy.

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

A significant correlation between saliva and plasma concentrations has been demonstrated in adults and children (plasma/saliva concentration ratio ranged from 1 to 1.7 after tablet administration and 4 hours after oral solution intake).

Adults and adolescents

Absorption

Levetiracetam is rapidly absorbed after oral administration. Absolute oral bioavailability is close to 100%. Maximum plasma concentration (Cmax) is reached within 1.3 hours after dosing. Steady-state is achieved within 2 days of twice-daily administration. Cmax 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 dose-independent and not affected by food.

Distribution

There are no data on tissue distribution in humans. Neither levetiracetam nor its primary metabolite bind significantly to plasma proteins (< 10%). The volume of distribution of levetiracetam ranges from 0.5 to 0.7 L/kg, approximately equal to 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 primary metabolite, ucb L057. Hydrolysis of the acetamide group occurs in a wide range of cells, 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 dose), and the other by opening of the pyrrolidine ring (0.9% of dose).

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

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

In vitro studies showed that levetiracetam and its primary 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 effects on CYP1A2, SULT1E1, or UGT1A1. Levetiracetam caused slight induction of CYP2B6 and CYP3A4. In vitro data and in vivo interaction studies with oral contraceptives, digoxin, and warfarin indicate no significant enzyme induction in vivo. Therefore, drug interactions with other substances or vice versa are unlikely.

Elimination

The elimination half-life of the drug from plasma in adults is 7 ± 1 hours and is independent of dose, route of administration, or repeated dosing. Mean total clearance is 0.96 mL/min/kg.

The majority of the drug, approximately 95% of the dose, is excreted by the kidneys (about 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 primary 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 that levetiracetam is eliminated by glomerular filtration followed by tubular reabsorption, while the primary metabolite is also actively secreted by renal tubules 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), due to reduced renal function in this population (see section "Dosage and administration").

Renal impairment

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

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

Hepatic impairment

In patients with mild to moderate hepatic impairment, levetiracetam clearance is unchanged. In most patients with severe hepatic impairment, levetiracetam clearance is reduced by more than 50%, primarily due to concomitant renal insufficiency (see section "Dosage and administration").

Paediatric population: children aged 4–12 years

After a single oral dose (20 mg/kg) in children with epilepsy (aged 6 to 12 years), the elimination half-life of levetiracetam was 6 hours. Apparent clearance, corrected for body weight, was approximately 30% higher than in adults with epilepsy.

After repeated oral administration (20 to 60 mg/kg/day) in children with epilepsy (aged 4 to 12 years), levetiracetam was rapidly absorbed. Cmax was observed within 0.5–1.0 hours after dosing. Cmax and area under the plasma 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.

Clinical characteristics.

Indications.

Monotherapy (first-line treatment) 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 adjunctive therapy in the treatment of:

• Partial seizures with or without secondary generalization in adults, adolescents, 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, to other pyrrolidone derivatives, or to any excipient of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Antiepileptic drugs

Post-marketing clinical data from studies in adults indicate that levetiracetam does not affect serum concentrations of established antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone), and that antiepileptic drugs do not affect the pharmacokinetics of levetiracetam.

There is also no apparent evidence of clinically significant drug interactions in children, as in adults, receiving levetiracetam at doses up to 60 mg/kg/day.

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

Probenecid

Probenecid (500 mg four times daily) blocks tubular secretion, inhibits renal clearance of the main metabolite, but not of levetiracetam itself. However, the concentration of this metabolite remains low.

Methotrexate

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

Oral contraceptives. Other pharmacokinetic interactions

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) were unchanged. Levetiracetam at a daily dose of 2000 mg does not alter the pharmacokinetics of digoxin and warfarin; prothrombin time values remained unchanged. Conversely, digoxin, oral contraceptives, and warfarin do not affect the pharmacokinetics of levetiracetam when administered concomitantly.

Laxatives

In isolated cases, reduced efficacy of levetiracetam has been reported when osmotic laxative macrogol is taken concomitantly with 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 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 determining the dose of the medicinal product (see section "Dosage and administration").

Acute kidney injury

Very rarely, acute kidney injury has been reported with levetiracetam use, with onset ranging from several days to several months.

Blood laboratory tests

With levetiracetam administration, rare cases of blood cell count reduction (neutropenia, agranulocytosis, leukopenia, thrombocytopenia, and pancytopenia) have generally been observed initially. Complete blood count is recommended for patients presenting with significant weakness, fever, recurrent infections, or coagulation disorders (see section "Adverse reactions").

Suicidal behaviour

Cases of suicide, suicide attempts, suicidal ideation, and suicidal behaviour 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 behaviour. The mechanism of this risk is not known.

Due to this risk, patients should be monitored for signs of depression and/or suicidal thoughts and behaviour, and treatment adjustments made if necessary. Patients (or their caregivers) should be advised to report any symptoms of depression and/or suicidal ideation or behaviour to their physician.

Unusual or aggressive behaviour

Levetiracetam may cause psychiatric symptoms and behavioural 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 behaviour occurs, treatment adaptation or gradual discontinuation is recommended. For discontinuation, see section "Dosage and administration".

Worsening of seizures

As with other antiepileptic medicinal products, levetiracetam use 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 was reversible upon discontinuation of the medicinal product or dose reduction. Patients should be advised to seek immediate medical advice if worsening of epilepsy occurs.

For example, inadequate efficacy or worsening of seizures has been observed in patients with epilepsy associated with mutations in the alpha subunit of voltage-gated sodium channels.

Prolongation of QT interval on electrocardiogram (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 QT interval prolongation, in patients concurrently taking medicinal products affecting the QT interval, and in patients with underlying cardiac conditions or electrolyte imbalances.

Children

The tablet formulation is not suitable for administration to infants and children under 6 years of age.

Available data in children do not indicate effects on development and sexual maturation. However, the potential impact on cognitive function, growth, endocrine system, and sexual maturation with levetiracetam use in children remains unknown.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Specific advice should be given to women of childbearing potential. Treatment with levetiracetam should be reviewed if a woman is planning pregnancy. As with all antiepileptic drugs, abrupt discontinuation of levetiracetam should be avoided, as this may lead to seizure occurrence, which could have serious consequences for both the woman and the unborn child.

Where possible, monotherapy should be preferred, as treatment with multiple antiepileptic drugs may be associated with a higher risk of congenital malformations than monotherapy, depending on the drug combination.

Pregnancy

Large amounts of post-marketing data from pregnant women using levetiracetam (more than 1800 women, including 1500 women exposed during the first trimester) do not indicate an increased risk of major congenital malformations. There is only limited information 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 disorders or delayed development of the nervous system. Levetiracetam may be used during pregnancy if, after careful evaluation, 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. This decrease is most pronounced in the third trimester (up to 60% of the pre-pregnancy baseline concentration). Adequate clinical monitoring should be ensured for pregnant women receiving levetiracetam.

Breastfeeding period

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

Fertility

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

Ability to influence reaction speed when driving or operating machinery.

Levetiracetam has a minor or moderate effect 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 when engaging in activities requiring high concentration, such as driving a car or operating machinery. Patients are advised to refrain from driving vehicles and operating machinery until it is established that their ability to perform such activities is not impaired.

Method of administration and dosage.

Tablets should be taken orally, swallowed with a sufficient amount of water, during meals or between meals. When taken orally, levetiracetam may have a bitter taste. The daily dose should be divided into 2 equal doses.

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 to 17 years) with body weight ≥ 50 kg

The initial therapeutic dose is 500 mg twice daily. This is the starting dose prescribed on the first day of treatment. However, the physician may prescribe a lower initial dose of 250 mg twice daily 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 a maximum of 1500 mg twice daily. Dose adjustments of 250 mg or 1000 mg/day (500 mg twice daily) may be made every 2–4 weeks.

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

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

Discontinuation of treatment

If discontinuation of the medication is necessary, it is recommended to taper off 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 dose by no more than 10 mg/kg twice daily every 2 weeks).

Special patient groups

Elderly patients (aged 65 years and older)

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

Renal impairment

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

For dose adjustment in adults, use the table below.

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

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

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

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

CrCl (mL/min)
CrCl (mL/min/1.73 m²) = --------------------------- × 1.73
BSA of patient (m²)

Table 1

Dosage regimen for adults and adolescents with renal impairment and body weight > 50 kg

Severity of renal impairment	Creatinine clearance (mL/min/1.73 m²)	Dosing regimen
Normal renal function	≥ 80	500 to 1500 mg twice daily
Mild impairment	50–79	500 to 1000 mg twice daily
Moderate impairment	30–49	250 to 750 mg twice daily
Severe impairment	< 30	250 to 500 mg twice daily
End-stage (patients on dialysis(1))	—	500 to 1000 mg once daily(2)

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

(2) 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 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 concentration (mg/dL) using the following formula (Schwartz formula):

      Height (cm) × ks
CrCl (mL/min/1.73 m²) = ------------------------------------------
    Serum creatinine (mg/dL)

For children under 13 years of age and adolescent females, ks = 0.55; for adolescent males, ks = 0.7.

Table 2
Dosage adjustment recommendations for children and adolescents with impaired renal function and body weight less than 50 kg

Severity of renal impairment	Creatinine clearance (mL/min/1.73 m²)	Children aged 6 years and older and adolescents with body weight less than 50 kg(1)
Normal renal function	≥ 80	10−30 mg/kg (0.10−0.30 mL/kg) twice daily
Mild	50–79	10–20 mg/kg (0.10–0.20 mL/kg) twice daily
Moderate	30–49	5–15 mg/kg (0.05–0.15 mL/kg) twice daily
Severe	< 30	5–10 mg/kg (0.05–0.10 mL/kg) twice daily
End-stage (patients on dialysis)		10–20 mg/kg (0.10–0.20 mL/kg) once daily (2)(3)

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

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 daily maintenance dose should be reduced by 50%.

Paediatric patients

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

The tablet formulation is not recommended for use in children under 6 years of age. Oral solution is preferred for this patient group. 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 the oral solution formulation.

Monotherapy

The safety and efficacy of Letram 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 seizures with or without secondary generalization, in whom epilepsy has been newly diagnosed

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

Oral solution of levetiracetam is preferred for infants and children under 6 years of age.

For children aged 6 years and older, oral solution of levetiracetam should be used for dosing up to 250 mg, for doses not divisible by 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 should be used. The initial dose for a child or adolescent weighing 25 kg should be 250 mg twice daily, with a maximum dose of 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

Infants should be treated with the oral solution formulation.

Children

The tablet formulation is not recommended for use in children under 6 years of age.

Levetiracetam oral solution should be used in infants from 1 month of age and in children under 6 years of age.

Overdose

Symptoms

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

Treatment

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

Adverse reactions

The most commonly reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue, and dizziness. The adverse reaction profile provided is based on a pooled analysis of data from placebo-controlled clinical trials across all indications, involving a total of 3416 patients who received levetiracetam. These data are supplemented by the use of levetiracetam in corresponding long-term open-label studies, as well as post-marketing experience.

The safety profile of levetiracetam is generally similar across age groups (adults and children) for the established epilepsy 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 Table 3 by system organ class and frequency of occurrence. Adverse reactions are presented in decreasing order of severity, and their frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100, <1/10); uncommon (≥ 1/1000, <1/100); rare (≥ 1/10,000, <1/1000); very rare (<1/10,000).

Table 3

MedDRA System Organ Classes	Frequency groups
	Very common	Common	Uncommon	Rare	Very rare
Infections and infestations	Nasopharyngitis			Infection
Blood and lymphatic system disorders			Thrombocytopenia, leukopenia	Pancytopenia, neutropenia, agranulocytosis
Immune system disorders				Drug reaction with eosinophilia and systemic symptoms (DRESS), hypersensitivity (including angioneurotic edema and anaphylaxis)
Metabolism and nutrition disorders		Anorexia	Increased or decreased body weight	Hypotremia
Psychiatric disorders		Depression, hostility/aggression, anxiety, insomnia, nervousness/irritability	Suicide attempt, suicidal thoughts, psychotic disorders, abnormal behavior, hallucinations, anger, confusion, panic attacks, affective lability/mood changes, agitation	Suicide, personality disorders, thought disorders, delirium	Obsessive-compulsive disorder**
Nervous system disorders	Somnolence, headache	Seizures, balance disorder, dizziness, lethargy, tremor	Amnesia, memory impairment, coordination disorder/ataxia, paresthesia, attention disorders	Choreoathetosis, dyskinesia, hyperkinesia, gait disturbance, encephalopathy, seizure exacerbation, neuroleptic malignant syndrome*
Eye disorders			Diplopia, blurred vision
Ear and labyrinth disorders		Vertigo
Cardiac disorders				QT interval prolongation on ECG
Respiratory, thoracic and mediastinal disorders		Cough
Gastrointestinal disorders		Abdominal pain, diarrhea, dyspepsia, vomiting, nausea		Pancreatitis
Hepatobiliary disorders			Abnormal liver function tests	Liver failure, hepatitis
Renal and urinary disorders				Acute kidney injury
Skin and subcutaneous tissue disorders		Rash	Alopecia, eczema, pruritus	Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme
Musculoskeletal and connective tissue disorders			Muscle weakness, myalgia	Rhabdomyolysis and elevated blood creatine phosphokinase*
General disorders		Asthenia/fatigue
Injury, poisoning and procedural complications			Injuries

* The prevalence 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 is higher when topiramate and levetiracetam are used concomitantly.

In some cases of alopecia, hair regrowth was observed after discontinuation of levetiracetam.

In some cases of pancytopenia, bone marrow suppression was observed.

In some cases of pancytopenia, bone marrow suppression was confirmed.

Cases of encephalopathy were usually observed at the beginning of treatment (from several days to several months) and were reversible after discontinuation of treatment.

Children

Among patients aged 1 month to 4 years, a total of 190 patients received levetiracetam treatment during placebo-controlled and open-label add-on studies. Of these, 60 patients received levetiracetam in placebo-controlled studies. Among patients aged 4–16 years, a total of 645 patients received levetiracetam treatment during placebo-controlled and open-label add-on studies. Of these, 233 patients received levetiracetam in placebo-controlled studies. In both age groups, these data are supplemented by post-marketing experience with levetiracetam use.

Additionally, in a post-marketing safety study, 101 infants under 12 months of age received treatment with the medicinal product. No new safety data on the use of levetiracetam in infants under 12 months of age with epilepsy were identified.

The adverse reaction profile of levetiracetam is generally similar across different age groups and all approved epilepsy indications. Safety results in children from placebo-controlled clinical trials were consistent with the safety profile of levetiracetam in adults, except for behavioral 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%), irritability (common, 3.4%), mood alteration (common, 2.1%), affective lability (common, 1.7%), aggression (common, 8.2%), behavioral abnormalities (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 disturbances (common, 3.3%) were observed more frequently than in other age groups or in the overall safety profile.

A safety study in children evaluated the effect of levetiracetam on cognitive and neuropsychological parameters in children aged 4 to 16 years with partial seizures. Levetiracetam did not differ from placebo (i.e., showed no inferiority) in changes from baseline on the "Attention and Memory—Leiter R" scale and total memory screening score in the per-protocol population. Results related to behavioral and emotional functions indicated increased aggressive behavior 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 function was observed on average, and aggressive behavior scores did not worsen compared to baseline.

Reporting of suspected adverse reactions

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Hetero Labs Limited.

Manufacturer's address and location of operations.

Unit III, Formulation Plot No 22 - 110 IDA, Jeedimetla, Hyderabad, 500 055 Telangana, India.