Lepsicad

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

Composition:

Active substance: levetiracetam;

1 tablet contains levetiracetam 250 mg or 500 mg or 750 mg or 1000 mg;

Excipients: povidone (E 1202), sodium croscarmellose, macrogol 6000, colloidal anhydrous silicon dioxide, magnesium stearate (E 470b);

Film coating:

250 mg tablets: polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), macrogol 3350, talc, indigo carmine aluminum lake (E 132);

500 mg tablets: polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), macrogol 3350, talc, iron oxide yellow (E 172);

750 mg tablets: polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), macrogol 3350, talc, sunset yellow aluminum lake (E 110), iron oxide red (E 172);

1000 mg tablets: polyvinyl alcohol partially hydrolyzed, titanium dioxide (E 171), macrogol 3350, talc.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties:

250 mg tablets: blue, elongated film-coated tablets, with a score line on one side and engraved “250” on the other;

500 mg tablets: yellow, elongated film-coated tablets, with a score line on one side and engraved “500” on the other;

750 mg tablets: orange, elongated film-coated tablets, with a score line on one side and engraved “750” on the other;

1000 mg tablets: white, elongated film-coated tablets, with a score line on one side and engraved “1000” on the other.

Pharmacotherapeutic group. Antiepileptic agents. 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. Based on in vitro and in vivo studies, it is presumed that levetiracetam does not alter the basic characteristics of nerve cells or normal neurotransmission. In vitro studies have shown that levetiracetam affects intraneuronal Ca2+ levels by partially inhibiting 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 have demonstrated that levetiracetam binds to specific sites in rodent brain tissues. The binding site is synaptic vesicle protein 2A (SV2A), which is involved in vesicle fusion and neurotransmitter release. The affinity (in rank order) of levetiracetam and its corresponding analogs for the synaptic vesicle protein 2A correlates with their anticonvulsant potency in models of audiogenic epilepsy in mice. These findings suggest that the interaction between levetiracetam and synaptic vesicle protein 2A may partially explain the antiepileptic mechanism of the drug.

Pharmacodynamic effects

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

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

Pharmacokinetics.

Levetiracetam is characterized by high solubility and permeability. Its pharmacokinetics are linear and characterized by low inter- and intrasubject variability. After repeated administration, clearance does not change. No 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 the drug can be predicted based on the oral dose of levetiracetam expressed in mg/kg body weight. Therefore, monitoring of plasma levels of levetiracetam is not necessary.

In adults and children, a significant correlation was observed between drug concentration in saliva and plasma (the saliva/plasma 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 approximately 100%. Peak plasma concentration (Cmax) is reached within 1.3 hours after drug intake. Steady-state is achieved within 2 days of twice-daily dosing. Peak concentrations (Cmax) typically reach 31 and 43 µg/mL after a single 1000 mg dose and repeated 1000 mg twice daily, respectively. The extent of absorption is independent of dose and is not altered by food intake.

Distribution.

There are no data on tissue distribution of the drug in humans. Neither levetiracetam nor its main metabolite bind significantly to plasma proteins (< 10%). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L/kg, which corresponds roughly 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 is not expected in vivo. Therefore, drug interactions between levetiracetam and 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.

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

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

Elderly patients.

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

Renal impairment.

The apparent total clearance of levetiracetam and its main metabolite correlates with creatinine clearance. Therefore, dose adjustment of the maintenance dose of levetiracetam is recommended for 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.

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

Pediatric population.

Children aged 4–12 years.

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

Clinical characteristics.

Indications.

Monotherapy (first-line agent) in the treatment of partial-onset seizures with or without secondary generalization in adults and adolescents aged 16 years and older who have newly diagnosed epilepsy.

As adjunctive therapy in the treatment of:

• partial-onset seizures with or without secondary generalization in adults and children aged 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 or to 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 clinical study data in adults indicate that levetiracetam does not affect serum concentrations of other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone), and these drugs in turn do not affect the pharmacokinetics of levetiracetam.

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

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

Probenecid.

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

Methotrexate.

It has been reported 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 drugs concomitantly.

Oral contraceptives and pharmacokinetic interactions with other drugs.

Levetiracetam at a daily dose of 1000 mg does not alter the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); endocrine parameters (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 administered concomitantly.

Laxatives.

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

Food and alcohol.

The extent of levetiracetam absorption is not affected by food, although the rate of absorption is slightly reduced when taken with food. There are no data on interactions 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 prior to dosing (see section "Dosage and administration").

Acute kidney injury.

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

Blood count.

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

Suicidal behaviour.

Suicidal tendencies, suicide attempts, suicidal thoughts, and suicidal behaviour 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 behaviour. The mechanism of this risk is not understood. Due to this risk, patients should be monitored for signs of depression and/or suicidal thoughts and behaviour, and treatment adjusted as necessary. Patients (or their caregivers) should be advised to inform their physician of any symptoms of depression and/or suicidal thoughts or behaviour.

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 adjustment or gradual discontinuation is recommended. For information on discontinuation, see section "Dosage and administration".

Prolongation of QT interval on ECG.

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

Exacerbation of seizures.

As with other antiepileptic drugs, levetiracetam may lead to increased frequency and severity of seizures. This paradoxical effect has mostly been reported within the first month after starting levetiracetam or increasing the dose, and is usually reversible upon discontinuation or dose reduction. Patients should be advised to contact their physician immediately if seizures worsen.

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 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 advice 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 this may provoke seizures, which could have serious consequences for both the woman and the unborn child. Monotherapy should be preferred when possible, since treatment with multiple antiepileptic drugs may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the combination used.

Pregnancy.

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

Physiological changes during pregnancy may affect levetiracetam concentrations. Decreased plasma concentrations of levetiracetam have been observed during pregnancy, with a more pronounced reduction in the third trimester (up to 60% of pre-pregnancy concentrations). Pregnant women receiving levetiracetam should be provided with appropriate clinical monitoring.

Breastfeeding.

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.

Effects on 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.

Effects on ability to drive and use machines.

Levetiracetam has a minor or moderate influence on the ability to drive and operate machinery. Due to possible individual sensitivity, some patients may experience somnolence or other central nervous system (CNS)-related symptoms, particularly at the beginning of treatment or during dose escalation. Therefore, such patients should exercise caution in activities requiring high attention, such as driving or operating machinery. Patients are advised to refrain from driving 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 sufficient fluid, with or without food. When administered orally, levetiracetam may have a bitter taste. The daily dose should be divided into 2 equal doses.

Monotherapy

Adults and adolescents aged 16 years and older

Monotherapy in adults and adolescents aged 16 years and older should be initiated at a dose of 500 mg/day (250 mg twice daily). After 2 weeks, the dose may be increased to the initial therapeutic dose of 1000 mg/day (500 mg twice daily). Thereafter, the dose may be increased by 250 mg twice daily every two weeks, depending on clinical response. The maximum daily dose is 3000 mg/day (1500 mg twice daily).

Children and adolescents under 16 years of age

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

Data are lacking.

Adjunctive Therapy

The physician should select the most appropriate dosage form, route of administration, and frequency of dosing based on age, body weight, and dose required.

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

The initial therapeutic dose is 1000 mg/day (500 mg twice daily). Treatment may be initiated at this dose on the first day.

Depending on clinical response and tolerability, the daily dose may be increased up to 3000 mg/day (1500 mg twice daily). The dose may be increased or decreased by 1000 mg/day (500 mg twice daily) every 2–4 weeks.

Adjunctive therapy in children aged 6 years and older and adolescents (aged 12 to 17 years) with body weight <50 kg.

Infants and children under 6 years of age should preferably be treated with the medicinal product in the form of oral solution.

Oral solution of levetiracetam should be used in children aged 6 years and older for doses below 250 mg, for doses not multiples of 250 mg, when the recommended dosing cannot be achieved by taking whole tablets, and for patients unable to swallow tablets.

The lowest effective dose should be used. The initial dose for a child or adolescent with a body weight of 25 kg should be 250 mg twice daily, with a maximum dose of 750 mg twice daily.

Children with body weight above 50 kg should receive dosing according to the adult regimen.

Adjunctive therapy in infants aged 1 to 6 months.

Infants should be treated with the medicinal product in the form of oral solution.

Discontinuation of Treatment

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

Special Patient Populations

Elderly patients (≥65 years)

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

Patients with Renal Impairment

The daily dose of levetiracetam should be individually adjusted.

In adult patients, the dose should be adjusted as shown in Table 3 below. To adjust the dose, the patient's creatinine clearance (CrCl) in mL/min must be determined.

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

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

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

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

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

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

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

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

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

   height (cm) × ks
eGFR (mL/min/1.73 m²) = ------------------------------ .
  serum creatinine (mg/dL)

In full-term infants under 1 year of age, ks = 0.45; in children up to 13 years of age and adolescent females, ks = 0.55; in adolescent males, ks = 0.7.

Dose adjustment recommendations for infants, children, and adolescents weighing
less than 50 kg with impaired renal function

(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 who are 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.

Patients with hepatic impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, creatinine clearance may not fully reflect the degree of renal impairment. Therefore, in patients with creatinine clearance < 60 mL/min/1.73 m², the daily maintenance dose should be reduced by 50%.

Children

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

The tablet formulation of the medicinal product is not recommended for children under 6 years of age. This patient group should preferably be treated with levetiracetam oral solution. Furthermore, 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.

Children

The tablet formulation of the medicinal product is not recommended for children under 6 years of age. Infants from 1 month of age and children under 6 years of age should be treated with levetiracetam oral solution.

Overdose

Symptoms

In cases of overdose with the drug Lepticard, somnolence, agitation, aggression, respiratory depression, depressed level of consciousness, and coma have been observed.

Treatment

In case of acute overdose, gastric lavage or induction of emesis should be performed. There is no specific antidote for levetiracetam. If necessary, symptomatic treatment should be administered, 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 described below is based on a pooled analysis of data from placebo-controlled clinical trials across all indications, involving a total of 3,416 patients who received levetiracetam. These data are supplemented by experience from relevant extended open-label studies and post-marketing experience. The safety profile of levetiracetam is generally similar across different age groups (adults and children) when used for the various approved indications.

Adverse reactions reported during clinical studies (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 order of decreasing frequency, and their incidence is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); and very rare (< 1/10,000).

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

Description of selected adverse reactions.

The risk of anorexia increases with concomitant use of levetiracetam and topiramate. In cases of alopecia, hair regrowth was observed in some instances after discontinuation of levetiracetam.

Cases of pancytopenia were sometimes associated with bone marrow suppression.

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 in 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 in placebo-controlled and open-label add-on studies. Of these, 233 patients received levetiracetam in placebo-controlled studies. In both age groups, these data were supplemented with post-marketing experience.

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

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 alteration (common, 2.1%), affective lability (common, 1.7%), aggression (common, 8.2%), abnormal behavior (common, 5.6%), and lethargy (common, 3.9%) were observed more frequently than in other age groups or in the overall safety profile. In infants and children aged 1 month to 4 years, irritability (very common, 11.7%) and coordination disturbances (common, 3.3%) occurred more frequently than in other age groups or in the overall safety profile.

In a double-blind, placebo-controlled safety study in children conducted to demonstrate non-inferiority of the drug, the effects of levetiracetam on cognitive and neuropsychological parameters were evaluated in children aged 4 to 16 years with partial seizures. The medicinal product Lepticard did not differ from placebo (was not inferior) regarding change from baseline in attention and memory as measured by the Leiter-R scale and total memory score in the per-protocol population. Results related to behavioral and emotional functions indicated increased aggressive behavior in patients treated with levetiracetam, as systematically and standardly assessed 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 functions was observed on average, including aggressive behavior scores which did not worsen from baseline.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life.

2 years.

Storage conditions.

Store at temperatures not exceeding 25°C, protected from light and out of reach of children.

Packaging.

10 tablets per blister. 3 blisters per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Jubilant Generics Limited.

Manufacturer's address and location of site of manufacture.

Sikandarpur Village, Bhainswal, Roorkee-Dehradun Highway, Bhagwanpur, District Roorkee Haridwar, Uttarakhand, IN-247661, India.