Krampalika

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KRAMPALIKA (CRAMPALIKA)

Composition:

Active substance: levetiracetam;

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

Excipients: calcium hydrogen phosphate dihydrate, microcrystalline cellulose, crospovidone (type A), hydroxypropylcellulose.

Film coating:

250 mg tablets: Opadry 02H20569 (blue): hypromellose, titanium dioxide (E 171), talc, propylene glycol, FD&C blue #2 aluminum lake (E 132), FD&C yellow #6 aluminum lake (E 110), quinoline yellow dye (E 104);

500 mg tablets: Opadry 20J22730 (yellow): hypromellose, titanium dioxide (E 171), hydroxypropylcellulose, propylene glycol, sorbitan oleate, sorbic acid, vanillin, quinoline yellow dye (E 104).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: Blue-colored, oblong, biconvex tablets without defects. Dimensions: 13.8 mm ± 0.1 mm by 6.7 mm ± 0.1 mm, thickness: 4.0 mm ± 0.2 mm;

500 mg tablets: Yellow-colored, oblong, biconvex tablets without defects.

Dimensions: 19.4 mm ± 0.1 mm by 7.8 mm ± 0.1 mm, thickness: 5.1 mm ± 0.2 mm.

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) that differs chemically from known antiepileptic drugs.

The mechanism of action of levetiracetam is not fully understood. Based on in vitro and in vivo studies, it is 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 demonstrated that levetiracetam binds to specific sites in brain tissues of rodents. The binding site is synaptic vesicle protein 2A (SV2A), which is involved in vesicle fusion and neurotransmitter release. The affinity (in rank order) of levetiracetam and its analogs for synaptic vesicle protein 2A correlated 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 action of the drug.

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

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

Pharmacokinetics.

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

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

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 concentrations are 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 ranges from 0.5 to 0.7 L/kg, approximately equal to total body water.

Metabolism.

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

Two minor metabolites have also been identified. One is formed by hydroxylation of the pyrrolidone ring (1.6% of dose), and the other by opening of the pyrrolidone ring (0.9% of dose). Other unidentified components accounted for only 0.6% of the dose. No interconversion of enantiomers of levetiracetam or its main metabolite was observed under in vivo conditions.

In vitro studies showed that levetiracetam and its main metabolite do not inhibit the activity of major 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 conjugation of CYP1A1/2, SULT1E1, or UGT1A1. Levetiracetam causes 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 unlikely in vivo. Therefore, drug interactions between Krampalika and other substances, or vice versa, are unlikely.

Elimination.

The elimination half-life of the drug from plasma in adults is 7±1 hour 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, on average 95% of the dose, is excreted by the kidneys (approximately 93% of the dose is excreted within 48 hours). Only 0.3% of the dose is excreted in feces.

Cumulative urinary excretion of levetiracetam and its main metabolite was 66% and 24% of the dose, respectively, within the first 48 hours. Renal clearance of levetiracetam and ucb L057 is 0.6 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 excreted via active tubular secretion in addition to glomerular filtration. Elimination of levetiracetam correlates with creatinine clearance.

Elderly patients.

In elderly patients, elimination half-life increases by approximately 40% (10–11 hours), which is associated with 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 is recommended for patients with moderate to severe renal impairment according to creatinine clearance (see section "Dosage and administration"). In patients with anuria in end-stage renal disease, 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 to 12 years), the elimination half-life of levetiracetam was 6 hours. Apparent clearance, corrected for body weight, was approximately 30% higher than in adult patients with epilepsy. After repeated oral administration (20–60 mg/kg/day) in children with epilepsy (aged 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 plasma 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 treatment) in the treatment of:

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

As adjunctive therapy in the treatment of:

• Partial-onset 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 or to other pyrrolidone derivatives, as well as to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Antiepileptic drugs.

Pre-registration clinical trial data in adult patients indicate that levetiracetam does not affect serum concentrations of established 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 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 steady-state serum concentrations of concomitantly administered carbamazepine and valproate. 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), a drug that blocks tubular secretion, inhibits the renal clearance of the main metabolite but not of levetiracetam itself. However, concentrations of this metabolite remain low.

Methotrexate.

It has been reported that concomitant use of levetiracetam and methotrexate reduces methotrexate clearance, leading to increased and/or prolonged methotrexate blood concentrations reaching 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 (levels of luteinizing hormone and progesterone) were unchanged. Levetiracetam at a daily dose of 2000 mg does not alter the pharmacokinetics of digoxin and warfarin; prothrombin time values remained unchanged. Digoxin, oral contraceptives, and warfarin 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 taken orally with levetiracetam. Therefore, macrogol should not be taken orally within 1 hour before or 1 hour after taking levetiracetam.

Food and alcohol.

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

Special precautions for use.

Renal impairment.

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

Acute kidney injury.

Very rare cases of acute kidney injury have been reported with levetiracetam, occurring from several days to several months after initiation of treatment.

Complete 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. Complete blood count monitoring is recommended in patients presenting with marked weakness, fever, recurrent infections, or bleeding disorders (see section "Adverse reactions").

Suicidal behaviour.

Suicide attempts, suicidal ideation, 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 has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Therefore, patients should be monitored for signs of depression and/or suicidal thoughts and behaviour, and treatment should be adjusted if necessary. Patients (and their caregivers) should be advised to promptly 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 adjustment or gradual discontinuation should be considered. For information on discontinuation, see the "Dosage and administration" section.

Exacerbation of seizures.

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

QT interval prolongation on ECG.

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

Children.

The film-coated tablet formulation of the medicinal product is not suitable for use in infants and children under 6 years of age.

Available data in children do not indicate an effect 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 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 provoke 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 may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the drug combination used.

Pregnancy.

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

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

Breastfeeding.

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.

Effect on fertility.

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

Ability to 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 or other central nervous system-related symptoms, particularly at the beginning of treatment or during dose escalation. 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 or operating machinery until it is established that their ability to perform such activities is not impaired.

Dosage and Administration.

Tablets should be taken orally, with sufficient liquid, with or without food. When administered 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 (aged 12–17 years) with body weight ≥50 kg. The initial therapeutic dose is 500 mg twice daily. This is the starting dose to be administered on the first day of treatment. However, a lower initial dose of 250 mg twice daily may be used at the physician’s discretion based on balancing seizure frequency reduction against potential adverse effects. 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 a maximum of 1500 mg twice daily. Dose adjustments of 250 mg or 500 mg twice daily may be made every 2–4 weeks.

Children aged 6 years and older and adolescents (aged 12–17 years) with body weight <50 kg. The physician should select the most appropriate dosage form, strength, and formulation based on body weight, age, and required dose. For dosage adjustment according to body weight, see section "Children".

Monotherapy.

The safety and efficacy of using the medicinal product as monotherapy in children and adolescents under 16 years of age have not been established. Data are lacking.

Adults and adolescents aged 16 years and older.

Monotherapy in adults and patients aged 16 years and older should be initiated at the recommended dose of 500 mg/day (250 mg twice daily), with subsequent increase of the initial therapeutic dose to 1000 mg/day (500 mg twice daily) after 2 weeks. Dose increases of 500 mg/day (250 mg twice daily) may be made every 2 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 using Keppralika as monotherapy in children and adolescents under 16 years of age have not been established. Data are lacking.

Adjunctive therapy.

Adjunctive therapy in adults (≥18 years) and adolescents (aged 12–17 years) with body weight ≥50 kg.

The initial therapeutic dose is 1000 mg/day (500 mg twice daily). This is the starting dose administered on the first day of treatment. Depending on clinical response and tolerability, the daily dose may be increased up to a maximum of 3000 mg/day (1500 mg twice daily). Dose adjustments of 1000 mg/day (500 mg twice daily) may be made every 2–4 weeks.

Adjunctive therapy in children aged 6 years and older and adolescents (aged 12–17 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.

Children aged 6 years and older should be treated with levetiracetam oral solution when dose adjustments below 250 mg are required, when the recommended dosage cannot be achieved by taking whole tablets, or 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.

For children with body weight exceeding 50 kg, dosing should follow the adult regimen. See the section above "Adults (≥18 years) and adolescents (12–17 years) with body weight ≥50 kg" for all indications.

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 the medicinal product is required, it is recommended to taper off gradually (e.g., for adults and adolescents with body weight ≥50 kg – reduce 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 in 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 provided below.

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

CrCl in adults and adolescents with body weight >50 kg can be calculated from serum creatinine concentration (mg/dL) 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 for body surface area (BSA) as follows:

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

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

Table 1

(1) On the first day of treatment with levetiracetam, a loading dose of 750 mg is recommended. (2) An additional dose of 250–500 mg is recommended after dialysis.

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

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

Height (cm) × ks
CC (ml/min/1.73 m²) = --------------------------------- .
Serum creatinine (mg/dl)

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

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

Table 2

(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.

Hepatic impairment.

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

Children.

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

The tablet form of the medicinal product is not recommended for use in children under 6 years of age. This patient group should preferably be treated with levetiracetam oral solution. Additionally, the available tablet strengths are not suitable for initial treatment of children weighing less than 25 kg, for patients unable to swallow tablets, or for doses below 250 mg. In all the above cases, treatment should be initiated with levetiracetam oral solution.

Children.

The tablet form of the medicinal product is not recommended for use in children under 6 years of age.

Overdose.

Symptoms.

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

Treatment.

In 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 the use of 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 is based on pooled 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 different age groups (adults and children) when used for various approved 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 listed in order of decreasing frequency within each system organ class, and their frequency is defined as follows: 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 3

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

** Very rare cases of development of obsessive-compulsive disorder (OCD) have been observed during post-marketing surveillance in patients with OCD or psychiatric disorders in medical history.

Description of selected adverse reactions.

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

In cases of pancytopenia, bone marrow suppression has been observed in some cases. Encephalopathy cases 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. 60 of these patients received levetiracetam treatment 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. 233 of these patients received levetiracetam treatment in placebo-controlled studies. For both age groups mentioned, these data are supplemented with post-marketing experience 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 with epilepsy under 12 months of age have been 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 are consistent with the safety profile of levetiracetam in adults, except for behavioral and psychiatric adverse reactions, which occurred more frequently 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%) were observed 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 effect of levetiracetam on cognitive and neuropsychological parameters was evaluated in children aged 4 to 16 years with partial seizures. The medicinal product containing levetiracetam did not differ (was not less effective) from placebo 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 determined systematically and standardized 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 not being worse than baseline. Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after marketing authorization of a medicinal product is an important procedure. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

No special temperature storage conditions are required for this medicinal product. Store out of reach of children.

Packaging.

10 tablets per blister; 3 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

FARMATEN S.A.

Manufacturer's address and location of its business operations.

Derivenakion 6, Pallini Attica, 15351, Greece