Keppra

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KEPRA® (Keppra®)

Composition:

Active substance: levetiracetam;

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

Excipients: sodium croscarmellose, macrogol 6000, colloidal anhydrous silicon dioxide, magnesium stearate;

Film coating:

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

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

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

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

250 mg tablets: elongated film-coated tablets of blue color with a break line; on one side of the break line, "ucb" is embossed, on the other side – "250";

500 mg tablets: elongated film-coated tablets of yellow color with a break line; on one side of the break line, "ucb" is embossed, on the other side – "500";

1000 mg tablets: elongated film-coated tablets of white color with a break line; on one side of the break line, "ucb" is embossed, on the other side – "1000".

Pharmacotherapeutic group. Antiepileptic drugs. Levetiracetam.

ATC code N03A X14.

Pharmacological Properties.

Pharmacodynamics.

The active substance, levetiracetam, is a pyrrolidone derivative (the S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine-acetamide) whose chemical structure is distinct 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 assumed that levetiracetam does not alter fundamental neuronal characteristics or normal neurotransmission. In vitro studies have shown that levetiracetam affects intraneuronal Ca2+ levels by partially inhibiting Ca2+ influx through N-type calcium channels and reducing Ca2+ release from intraneuronal stores. It also partially counteracts the inhibition of GABA- and glycine-regulated currents induced by zinc and β-carbolines. Furthermore, in vitro studies demonstrated that levetiracetam binds to specific sites in rodent brain 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 analogs for synaptic vesicle protein 2A correlates with their anticonvulsant potency in mouse models of audiogenic epilepsy. These findings suggest that the interaction between levetiracetam and synaptic vesicle protein 2A may partially explain the drug's antiepileptic mechanism of action.

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 exhibit 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 levels of the drug can be predicted from the oral dose of levetiracetam expressed in mg/kg body weight. Therefore, monitoring plasma levels of levetiracetam is not necessary.

In adults and children, a strong correlation was observed between drug concentrations in saliva and plasma (the saliva/plasma concentration ratio ranged from 1 to 1.7 after administration of tablets for oral use and 4 hours after 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 dose-independent and is not altered by food intake.

Distribution.

Data on tissue distribution in humans are lacking. Neither levetiracetam nor its primary metabolite bind significantly to plasma proteins (<10%). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L/kg, which corresponds to the total body water volume.

Metabolism.

Levetiracetam metabolism in humans is minimal. The primary 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 results from hydroxylation of the pyrrolidone ring (1.6% of the dose), and the other from 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 primary metabolite was observed under in vivo conditions.

In vitro studies showed that levetiracetam and its primary metabolite do not inhibit the activity of major 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 unlikely in vivo. Therefore, drug interactions between Keppra® and other substances, or vice versa, are unlikely.

Elimination.

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

The majority of the drug, on average 95% of the dose, is excreted in urine (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 primary metabolite was 66% and 24% of the dose, respectively, within the first 48 hours. Renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 mL/min/kg, respectively, indicating that levetiracetam is eliminated by glomerular filtration followed by tubular reabsorption, and that the primary metabolite is also eliminated via 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 associated with impaired renal function in this population (see section "Dosage and administration").

Renal impairment.

The apparent total clearance of levetiracetam and its primary metabolite correlates with creatinine clearance. Therefore, dose adjustment of the maintenance dose of Keppra® 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 standard 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%, primarily 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 seizures with or without secondary generalization in adults and adolescents aged 16 years and older with newly diagnosed epilepsy.

As adjunctive therapy in the treatment of:

• Partial seizures with or without secondary generalization in adults, adolescents, and children aged 6 years and older with epilepsy;
• Myoclonic seizures in adults and adolescents aged 12 years and older with juvenile myoclonic epilepsy;
• Primary generalized tonic-clonic seizures in adults and adolescents aged 12 years and older with idiopathic generalized epilepsy.

Contraindications.

Hypersensitivity to levetiracetam 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 established antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone), and these drugs do not affect the pharmacokinetics of levetiracetam.

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

A retrospective evaluation of pharmacokinetic interactions in children and adolescents with epilepsy (aged 4 to 17 years) confirmed that adjunctive therapy with oral levetiracetam did not affect the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data indicate that the clearance of levetiracetam is 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/prolonged methotrexate blood concentrations to potentially toxic levels. Methotrexate and levetiracetam blood levels should be closely monitored in patients receiving both drugs simultaneously.

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) 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 individual cases, reduced efficacy of levetiracetam has been reported when co-administered with the osmotic laxative macrogol taken orally with oral levetiracetam. Therefore, macrogol should not be taken orally within one hour before or one 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 interactions between levetiracetam and 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 dose of the medicinal product (see section "Dosage and administration").

Acute kidney injury.

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

Complete blood count.

Rare cases of blood cell count reduction (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 significant weakness, fever, recurrent infections, or coagulation disorders (see section "Adverse reactions").

Suicidal behaviour.

Suicide, suicide attempts, suicidal ideation, and suicidal behaviour have been observed in patients treated with antiepileptic medicinal products (including levetiracetam). A meta-analysis of results from randomized placebo-controlled trials of antiepileptic drugs showed a small increased risk of suicidal thoughts and behaviour. The mechanism by which this risk may arise has not been established. Due to the existence of such risk, 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 inform their physician about 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 adaptation or gradual discontinuation is recommended. For information on discontinuation, see section "Dosage and administration".

Worsening of seizures.

As with other antiepileptic medicinal products, levetiracetam use may rarely increase the frequency or severity of seizures. This paradoxical effect has most frequently been reported during the first month after initiation of levetiracetam or during dose escalation. This effect was reversible upon discontinuation of the medicinal product or dose reduction. Patients should be advised to seek immediate medical advice if worsening of seizures occurs. For example, inadequate efficacy or worsening of seizures has been reported in patients with epilepsy associated with mutations in the alpha subunit of voltage-gated sodium channels.

Prolongation of QT interval on electrocardiogram (ECG).

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

Children.

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

Available data in children do not indicate 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 recommendations should be provided to women of childbearing potential. Treatment with levetiracetam should be reviewed if a woman is planning pregnancy. As with all antiepileptic medicinal products, abrupt discontinuation of levetiracetam should be avoided, as this may lead to seizure occurrence, which could have serious consequences for both the woman and the unborn child. Monotherapy should be preferred whenever possible, as treatment with multiple antiepileptic medicinal products may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the combination of drugs used.

Pregnancy.

A large amount of post-marketing data from pregnant women who used levetiracetam (over 1800 women, of whom 1500 used the drug during the first trimester) does not indicate an increased risk of major congenital malformations. There is only limited data available on the neurodevelopmental outcomes of children exposed to monotherapy with Keppra® 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. This reduction is most pronounced in the third trimester (up to 60% of the pre-pregnancy baseline concentration). Adequate clinical monitoring of pregnant women receiving levetiracetam should be ensured.

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 reproductive function.

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

Ability to affect reaction speed when driving or operating machinery.

Levetiracetam has a minor or moderate influence on the ability to drive and use machinery. Due to possible individual sensitivity, some patients may experience somnolence or other symptoms related to central nervous system effects, particularly at the beginning of treatment or during dose escalation. Therefore, such patients should exercise caution when engaging in activities requiring high concentration, such as driving a car or operating machinery. Patients are advised to refrain from driving vehicles 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, 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.

Partial seizures

The recommended dose for monotherapy (patients aged 16 years and older) and adjunctive therapy is the same and is indicated below.

All indications

Adults (≥ 18 years) and adolescents (aged 12 to 17 years) with body weight ≥ 50 kg.

The initial therapeutic dose is 500 mg twice daily. This is the initial dose administered on the first day of treatment. However, a lower initial dose of 250 mg twice daily may be used at the physician’s discretion based on an assessment of seizure frequency reduction versus potential adverse effects. This dose may be increased to 500 mg twice daily after 2 weeks.

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

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

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

Discontinuation of treatment.

If discontinuation of the drug is necessary, it is recommended to withdraw it gradually (e.g., for adults and adolescents with body weight ≥ 50 kg – reduce the dose by 500 mg twice daily every 2–4 weeks; for children and adolescents with body weight < 50 kg – reduce the dose by no more than 10 mg/kg twice daily every 2 weeks).

Special patient groups.

Elderly patients (aged 65 years and older).

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

Renal impairment.

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

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

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

CrCl in adults and adolescents with body weight > 50 kg can be calculated from 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)

Table 1

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

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

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

For children with renal impairment, the dose of levetiracetam should be adjusted according to renal function, as 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, GFR 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
GFR (ml/min/1.73 m²) = --------------------------------- .
Serum creatinine (mg/dl)

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

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

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

(2) On the first day of treatment, a loading dose of levetiracetam 15 mg/kg (0.15 mL/kg) is recommended.

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

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 presentation based on age, body weight, and calculated dose.

The tablet formulation is not recommended for children under 6 years of age. This patient group should preferably be treated with Keppra® 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 aforementioned cases, treatment should be initiated with Keppra® oral solution.

Monotherapy

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

Data are lacking.

Adolescents (16–17 years of age) weighing ≥ 50 kg with partial-onset seizures with or without secondary generalization, newly diagnosed with epilepsy

See section above «Adults (≥ 18 years) and adolescents (12–17 years) weighing ≥ 50 kg».

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

Infants and children under 6 years of age should preferably be treated with Keppra® oral solution.

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

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

Children weighing more than 50 kg should receive dosing according to the regimen described for adults.

See section above «Adults (≥ 18 years) and adolescents (12–17 years) weighing ≥ 50 kg» for all indications.

Adjunctive therapy in infants aged 1 to 6 months

Infants should be treated with the oral solution formulation.

Children.

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

Overdose.

Symptoms.

Overdose with Keppra® has been associated with somnolence, agitation, aggression, respiratory depression, impaired consciousness, and coma.

Treatment.

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

Adverse reactions

The most commonly reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue, and dizziness. The adverse reaction profile presented is based on a pooled analysis of data from placebo-controlled clinical trials across all indications, involving a total of 3416 patients who received levetiracetam. These data are supplemented by the use of levetiracetam in corresponding long-term open-label studies, as well as post-marketing experience. The safety profile of levetiracetam is generally similar across different age groups (adults and children) when used for various approved indications.

Adverse reactions reported in 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 severity, and their frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); and very rare (< 1/10,000).

Table 3

1 See below "Description of selected adverse reactions".

2 During post-marketing surveillance, very rare cases of development of obsessive-compulsive disorders (OCD) were observed in patients with OCD or psychiatric disorders in medical history.

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

Description of selected adverse reactions

Multi-organ hypersensitivity reactions

Multi-organ hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)) have been rarely reported in patients receiving levetiracetam. Clinical manifestations may develop 2–8 weeks after initiation of treatment. These reactions are variable in presentation but usually associated with fever, rash, facial swelling, lymphadenopathy, hematological abnormalities, and may involve multiple organ systems, predominantly the liver. Levetiracetam should be discontinued if multi-organ hypersensitivity reaction is suspected.

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

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

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

Children.

A total of 190 patients aged 1 month to 4 years 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. Data in both age groups 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 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 disorders (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 effects of levetiracetam on cognitive and neuropsychological parameters were evaluated in children aged 4 to 16 years with partial seizures. Keppra® 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 instruments (CBCL – Achenbach Child Behavior Checklist). However, in patients receiving levetiracetam in a long-term open-label follow-up study, no average worsening of behavioral and emotional functions was observed, including aggressive behavior scores which were not worse than baseline.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmacy 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 reach of children.

Packaging.

10 tablets in a blister; 3 or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

UCB Pharma, Belgium /
UCB Pharma, Belgium.

Manufacturer's address and location.

Chemin Du Foriest 1, Braine-L’alleud, 1420, Belgium /
Chemin Du Foriest 1, Braine-L’alleud, 1420, Belgium.

Marketing Authorization Holder.

UCB Pharma S.A., Belgium /
UCB Pharma S.A., Belgium.

Address of the Marketing Authorization Holder.

Allee de la Recherche 60, B-1070 Bruxelles, Belgium /
Allee de la Recherche 60, B-1070 Bruxelles, Belgium.