Letram

INSTRUCTIONS for medical use of the medicinal product LETRAM (LETRAM)

Composition:

Active substance: levetiracetam;

1 ml contains 100 mg of levetiracetam;

Excipients: sodium chloride, sodium acetate trihydrate, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical characteristics: clear, colourless solution.

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) that differs chemically from 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. In vitro and in vivo experiments suggest 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. Additionally, it 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 an ordered affinity for binding to synaptic vesicle protein 2A, which correlates with their anticonvulsant activity in an 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 has been demonstrated in both partial and generalized forms of epilepsy (epileptiform discharges / photoparoxysmal response), confirming the broad pharmacological profile of levetiracetam.

Pharmacokinetics.

The pharmacokinetic (PK) profile after intravenous administration is described as corresponding to the PK profile after oral administration. A single 1500 mg dose of levetiracetam, diluted in 100 mL of a compatible diluent and administered intravenously over 15 minutes, is bioequivalent to a 1500 mg oral dose of levetiracetam given as three 500 mg tablets.

Pharmacokinetic and safety profiles of doses up to 2500 mg and 4000 mg, diluted in 100 mL of 0.9% sodium chloride and administered intravenously over 5 and 15 minutes, respectively, were evaluated and revealed no safety concerns.

Levetiracetam is a highly soluble compound with high permeability. The pharmacokinetic profile is linear with low inter-individual variability. No changes in clearance are observed after repeated administration. Time-independent PK profile of levetiracetam has been confirmed by intravenous administration of 1500 mg (twice daily) over 4 days. There is no evidence of any changes related to sex, race, or circadian rhythm. The pharmacokinetic profile is comparable between healthy volunteers and patients with epilepsy.

Adults and adolescents.

Distribution. There are no data on tissue distribution of the drug in humans.

Neither levetiracetam nor its primary metabolite binds significantly to plasma proteins (<10%). The volume of distribution of levetiracetam is approximately 0.5–0.7 L/kg, which is close to the value of total body water.

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 variety of cells, 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 the dose), and the other by opening of the pyrrolidine 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 have shown 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 effects on CYP1A2, SULT1E1, or UGT1A1. Levetiracetam caused slight induction of CYP2B6 and CYP3A4. In vitro data and in vivo interaction data with oral contraceptives, digoxin, and warfarin indicate no significant enzyme induction in vivo. Therefore, drug interactions with 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.

The main route of elimination is via urine, with approximately 95% of the dose excreted (about 93% within 48 hours). Fecal excretion accounts for only 0.3% of the dose.

Cumulative urinary excretion of levetiracetam and its main metabolite is 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 main metabolite is also eliminated by active tubular secretion in addition to glomerular filtration. Levetiracetam elimination correlates with creatinine clearance.

Elderly patients.

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

Renal impairment.

The observed total clearance of levetiracetam and its main metabolite correlates with creatinine clearance. Therefore, for patients with moderate to severe renal impairment, adjustment of the maintenance daily dose of levetiracetam is recommended 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, no significant changes in levetiracetam clearance occur. In most patients with severe hepatic impairment, levetiracetam clearance is reduced by more than 50%, primarily due to concomitant renal impairment (see section "Dosage and administration").

Paediatric population.

Children aged 4–12 years.

Pharmacokinetics in children after intravenous administration has not been studied. However, based on the pharmacokinetic characteristics of levetiracetam in adults after intravenous administration and on pharmacokinetics in children after oral administration, exposure (AUC) to levetiracetam is expected to be similar in children aged 4 to 12 years after both intravenous and oral administration.

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, adjusted 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. Peak plasma concentrations were observed 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; apparent total clearance was 1.1 mL/min/kg.

Clinical characteristics.

Indications.

Levetam is indicated as monotherapy for the treatment of partial onset seizures, with or without secondary generalization, in adults and adolescents aged 16 years and older with newly diagnosed epilepsy.

Levetam is indicated as adjunctive therapy:

• for partial onset seizures, with or without secondary generalization, in adults, adolescents and children aged 4 years and older with epilepsy;
• for myoclonic seizures in adults and adolescents aged 12 years and older with juvenile myoclonic epilepsy;
• for primary generalized tonic-clonic seizures in adults and adolescents aged 12 years and older with idiopathic generalized epilepsy.

Levetam concentrate is an alternative for patients when oral administration is temporarily not feasible.

Contraindications.

Hypersensitivity to levetiracetam or to other pyrrolidone derivatives, or to any excipient.

Interaction with other medicinal products and other forms of interaction.

Antiepileptic drugs.

Pre-registration clinical study data in adults indicate that levetiracetam does not affect serum concentrations of concomitant antiepileptic agents (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone), and that antiepileptic drugs do not influence the pharmacokinetics of levetiracetam.

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

A retrospective assessment of drug interaction pharmacokinetics in children with epilepsy (aged 4 to 17 years) confirmed that adjunctive oral levetiracetam therapy did not affect steady-state serum concentrations when co-administered with carbamazepine and valproate. However, data suggest that the clearance of levetiracetam may be 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 major metabolite, but not of levetiracetam itself. However, the concentration of this metabolite remains low.

Methotrexate.

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

Oral contraceptives and 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) remained 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.

Alcohol.

There are no data on the interaction between levetiracetam and alcohol.

Special precautions for use.

Renal impairment.

Dose adjustment is required when administering levetiracetam to patients with renal impairment. In patients with severe hepatic dysfunction, renal function should be assessed before determining the dose of the drug (see section "Dosage and administration").

Acute kidney injury.

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

Blood laboratory tests.

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

Suicidal behaviour.

Suicide attempts, suicidal ideation, and suicidal behaviour have been observed in patients treated with antiepileptic medicinal products, including levetiracetam. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs has shown an increased risk of suicidal thoughts and behaviour. The mechanism of this risk is unknown.

Therefore, patients should be monitored for the emergence of depression and/or suicidal thoughts and behaviour, and appropriate treatment should be provided. Patients (and caregivers) should be advised to consult their physician if symptoms of depression and/or suicidal thoughts or behaviour occur.

Unusual or aggressive behaviour.

Levetiracetam may cause psychiatric symptoms and behavioural disturbances, including irritability and aggression. Patients receiving levetiracetam should be monitored for the development of psychiatric signs indicating significant mood and/or personality changes. If such behaviour occurs, adjustment of treatment or gradual discontinuation is recommended. For instructions on discontinuation, see section "Dosage and administration".

Worsening of seizures.

As with other antiepileptic medicinal products, levetiracetam may rarely increase the frequency or severity of seizures. This paradoxical effect has most frequently been reported during the first month after initiation of levetiracetam or during dose escalation. This effect was reversible upon discontinuation of the drug 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 the 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 taking concomitant medicinal products that affect the QT interval, and in patients with relevant pre-existing cardiac conditions or electrolyte imbalances.

Children.

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

Excipients.

Letram contains 2.5 mmol (or 57 mg) of sodium per maximum single dose (0.8 mmol or 19 mg per vial). This should be taken into account if the patient is on a sodium-controlled diet.

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 medicinal products, abrupt discontinuation of levetiracetam should be avoided, as this may lead to convulsive seizures, which could have serious consequences for both the woman and the unborn child. Whenever possible, monotherapy should be preferred, since treatment with multiple antiepileptic drugs is associated with a higher risk of congenital malformations than monotherapy, depending on the combination of drugs used.

Pregnancy.

Large post-marketing data from pregnant women who used levetiracetam (over 1800 women, of whom 1500 used the drug 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 delay in nervous system development. Levetiracetam 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. The reduction in levetiracetam concentration is most pronounced in the third trimester (up to 60% of the pre-pregnancy concentration). Appropriate clinical monitoring is required for pregnant women undergoing treatment with levetiracetam.

Breastfeeding period.

Levetiracetam passes into human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam is necessary 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.

No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. 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 heightened attention, such as driving a car or operating machinery. Patients are advised to refrain from driving or operating machinery until it has been established that their ability to perform such activities is not impaired.

Dosage and Administration

Levetiracetam therapy can be initiated either intravenously or orally. Switching from oral to intravenous administration can be done directly without dose titration. The total daily dose and frequency of administration remain unchanged.

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 of 50 kg or more.

The initial therapeutic dose 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 prescribed by the physician based on a risk-benefit assessment regarding seizure frequency reduction versus potential adverse reactions. This dose may be increased to 500 mg twice daily after 2 weeks.

Depending on the clinical response and tolerability, the daily dose may be increased up to 1500 mg twice daily. Dose adjustments may be made by increasing or decreasing the dose by 250 mg or 500 mg twice daily every 2–4 weeks.

Adolescents (12 to 17 years) with body weight less than 50 kg and children aged 4 years and older.

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

Duration of treatment.

There is no experience with intravenous administration of levetiracetam for longer than 4 days.

Discontinuation of treatment.

If discontinuation of the drug 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 populations.

Elderly patients (aged 65 years and older).

Dosage adjustment in elderly patients should follow the same recommendations as for patients with renal impairment (see section "Renal Impairment").

Renal impairment.

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

For adults, adjust the dose as indicated in Table 1.

To adjust the dose using the table, the creatinine clearance (CrCl) in mL/min must be determined for the patient based on serum creatinine levels (mg/dL). CrCl for adults and adolescents with body weight over 50 kg is calculated using the formula:

Then, CC is adjusted according to body surface area (BSA) as shown below:

Table 1

Dose adjustment for adults and adolescents with body weight above 50 kg who have renal impairment

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

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

For children with impaired renal function, dosage adjustment of levetiracetam is required according to renal function status, as levetiracetam clearance is related to kidney function. This recommendation is based on a study involving patients with impaired renal function.

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

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

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

• On the first day of treatment with levetiracetam, a loading dose of 15 mg/kg (0.15 mL/kg) is recommended.
  • After dialysis, an additional dose of 5 to 10 mg/kg (0.05 to 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 pharmaceutical form, dosage strength, and presentation based on body weight, age, and dose.

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) with body weight ≥ 50 kg with partial onset seizures, with or without secondary generalization, with newly diagnosed epilepsy. See section above “Adults (≥ 18 years) and adolescents (12–17 years) with body weight ≥ 50 kg”.

Adjunctive therapy for children (4–11 years of age) and adolescents (12–17 years of age) with body weight < 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. The dose should not be increased or decreased by more than 10 mg/kg twice daily every two weeks. The lowest effective dose should be used for all indications.

Children with body weight of 50 kg or more should receive the same doses as adults (for all indications).

See section above “Adults (≥ 18 years) and adolescents (12–17 years) with body weight ≥ 50 kg” (for all indications).

Table 3

Dosage recommendations for children and adolescents

• For children with a body weight of 25 kg or less, treatment should be initiated with levetiracetam 100 mg/mL oral solution.
  • The dose for children and adolescents with a body weight of 50 kg is the same as that for adults.

Adjunctive therapy for children under 4 years of age. The safety and efficacy of levetiracetam concentrate for infusion solution in infants and children under 4 years of age have not been established.

Instructions for use, handling, and disposal

Letram is a concentrate for infusion solution, intended for intravenous use only. The recommended dose should be diluted in a diluent with a volume of not less than 100 mL and administered intravenously over 15 minutes.

Table 4 provides instructions for the preparation and administration of Letram concentrate for infusion to achieve a total daily dose of 500 mg, 1000 mg, 2000 mg, or 3000 mg; the daily dose should be divided into two administrations.

Table 4

Preparation and administration of Letram, concentrate for infusion solution

The medicinal product is intended for single use; any unused solution should be discarded.

The physical and chemical stability of the diluted concentrate for infusion has been demonstrated for 24 hours in PVC bags at 15–25 °C.

Solvents:

• 0.9 % sodium chloride solution for injection;
• Ringer's lactate solution for injection;
• 5 % glucose solution for injection.

Solutions containing particulate matter or showing discoloration should not be used. Any unused solution or waste material must be disposed of according to local requirements.

Infusion solution after dilution

From a microbiological standpoint, the product should be used immediately after dilution. If not used immediately, the user is responsible for the storage conditions and duration, which must not exceed 24 hours at a temperature not exceeding 25 °C, provided that dilution was carried out under controlled and aseptic conditions.

Children

The safety and efficacy of the medicinal product as monotherapy in children under 16 years of age have not been studied. There are no available data.

The safety and efficacy of levetiracetam administered as a concentrate for solution for infusion in infants and children under 4 years of age have not been established.

Overdose

Symptoms . Overdose of levetiracetam has been associated with somnolence, agitation, aggression, depression of consciousness, respiratory depression, and coma.

Treatment . Following acute overdose, gastric lavage and induction of emesis may be considered. There is no specific antidote for levetiracetam. Management should be symptomatic and may include hemodialysis. The clearance rate of levetiracetam is 60 %, and of its primary metabolite—74 %.

Adverse Reactions

The most commonly reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue, and dizziness. The adverse reaction profile described below is based on a pooled analysis of data from placebo-controlled clinical trials across all indications, involving a total of 3416 patients treated with levetiracetam. These data are supplemented by experience from appropriate long-term open-label studies and post-marketing experience. The safety profile of levetiracetam is generally similar across age groups (adults and children) for the established epilepsy indications. Since data on the intravenous administration of levetiracetam are limited and considering its bioequivalence, the safety information for intravenous levetiracetam is based on data from oral administration of the medicinal product.

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 5, classified by system organ classes and specified according to their frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); and very rare (< 1/10000).

Table 5

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

** Very rare cases of development of obsessive-compulsive disorders (OCD) have been reported during post-marketing surveillance 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 several cases of alopecia, recovery to normal condition was observed after discontinuation of levetiracetam.

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

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

A total of 190 patients aged 1 month to 4 years 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. Data from both age groups were supplemented with post-marketing safety data on levetiracetam use.

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

The adverse reaction profile of levetiracetam is generally similar across different age groups and all approved epilepsy indications. Safety results from placebo-controlled clinical trials in children 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 changes (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 disorders (common, 3.3%) occurred more frequently than in other age groups or in the overall safety profile.

A safety study in children evaluated the effects 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., was not inferior) in changes from baseline on the "Attention and Memory—Leiter R" scale and the 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 determined systematically and using validated tools (CBCL—Achenbach Child Behavior Checklist). However, in patients receiving levetiracetam in a long-term, open-label follow-up study, no overall worsening of behavioral and emotional function was observed on average, including no deterioration in aggressive behavior scores from baseline.

Reporting suspected adverse reactions

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through 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 °C.

Keep out of the reach of children.

Packaging.

5 ml (500 mg) in a vial, 1 or 10 vials per box.

Prescription status. Prescription only.

Manufacturer. Aspiro Pharma Limited.

Manufacturer's address and location of operations.

Sy.No.321, Biotech park, Phase-III, Karkapatla Village, Markook Mandal, Siddipet Dist-502281, Telangana State, India.