Levenium

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVENIUM LEVENIUM

Composition:

Active substance: levetiracetam;

One film-coated tablet contains levetiracetam 250 mg, 500 mg, 750 mg, or 1000 mg;

Excipients:

Tablets of 250 mg: maize starch, povidone, sodium croscarmellose, colloidal anhydrous silicon dioxide, talc, magnesium stearate, coating Opadry Blue 03B50622: hypromellose, titanium dioxide (E 171), polyethylene glycol 400, brilliant blue FCF aluminum lake (E 133);

Tablets of 500 mg: maize starch, povidone, sodium croscarmellose, colloidal anhydrous silicon dioxide, talc, magnesium stearate, coating Opadry Yellow 03F52321: hypromellose, titanium dioxide (E 171), polyethylene glycol 6000, talc, iron oxide yellow (E 172);

Tablets of 750 mg: maize starch, povidone, sodium croscarmellose, colloidal anhydrous silicon dioxide, talc, magnesium stearate, coating Opadry Orange 03B53743: hypromellose, titanium dioxide (E 171), polyethylene glycol 400, sunset yellow FCF aluminum lake (E 110), iron oxide red (E 172), indigo carmine aluminum lake (E 132);

Tablets of 1000 mg: maize starch, povidone, sodium croscarmellose, colloidal anhydrous silicon dioxide, talc, magnesium stearate, coating Opadry White YS-1-7003: titanium dioxide (E 171), hypromellose, polyethylene glycol 400, polysorbate 80.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets of 250 mg: capsule-shaped, biconvex film-coated tablets of blue color, smooth on one side and with a break line on the other;

Tablets of 500 mg: oval, biconvex film-coated tablets of light yellow color, smooth on one side and with a break line on the other;

Tablets of 750 mg: capsule-shaped, biconvex film-coated tablets of light orange color, smooth on one side and with a break line on the other;

Tablets of 1000 mg: oval, biconvex film-coated tablets of white color, smooth on one side and with a break line on the other.

Pharmacotherapeutic group.

Antiepileptic drugs. Levetiracetam. ATC code N03A X14.

Pharmacological Properties.

Pharmacodynamics.

Levetiracetam is a pyrrolidone derivative (S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine-acetamide) and differs chemically from known antiepileptic drugs.

The mechanism of action of levetiracetam is not fully understood, but it has been established that its mechanism differs from that of known antiepileptic agents. Based on in vitro and in vivo studies, levetiracetam is thought not to alter basic 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 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 drug's antiepileptic mechanism of action.

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/photoparoxysmal response), indicating a broad pharmacological profile of levetiracetam.

Pharmacokinetics.

Levetiracetam is characterized by high solubility and permeability. Its pharmacokinetics are linear, time-independent, and exhibit low inter- and intra-subject variability. After repeated administration, clearance does not change. No significant 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 plasma levels of levetiracetam is not necessary.

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

Adults and Adolescents

Absorption.

Levetiracetam is rapidly absorbed after oral administration. Absolute oral bioavailability is close to 100%. Peak plasma concentrations (Cmax) are reached within 1.3 hours after dosing. Steady-state concentrations are achieved within 2 days of twice-daily administration. 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 unaffected by food.

Distribution.

Data on tissue distribution in humans are limited. 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.

Metabolism of levetiracetam 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 various tissues, including blood cells. Metabolite ucb L057 is pharmacologically inactive.

Two minor metabolites have also been identified: one formed by hydroxylation of the pyrrolidone ring (1.6% of dose), and the other by ring opening of the pyrrolidone moiety (0.9% of dose).

Other unidentified components account 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. At high concentrations (680 µg/mL), levetiracetam caused weak induction of CYP2B6 and CYP3A4; however, at concentrations comparable to Cmax after repeated 1500 mg twice daily dosing, this effect was not biologically significant. 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, interactions between levetiracetam and other substances 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.

Approximately 95% of the administered dose is excreted by the kidneys (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 accounts for 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 by glomerular filtration followed by tubular reabsorption, while the main metabolite is also excreted 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 associated with reduced 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 maintenance levetiracetam dosage is recommended for patients with moderate to severe renal impairment based on creatinine clearance (see section "Dosage and Administration").

In patients with end-stage renal disease and anuria, 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.

The pharmacokinetics of levetiracetam are not altered in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). In patients with severe hepatic impairment (Child-Pugh class C), total clearance is 50% lower than in patients with normal liver function, but this is primarily due to concomitant reduction in renal clearance (see section "Dosage and Administration").

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 severity of renal dysfunction. Therefore, if creatinine clearance is <60 mL/min/1.73 m², the maintenance daily dose should be reduced by 50% (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. 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 (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 agent) in the treatment of:

• Partial seizures with or without secondary generalization in adults and children 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 and children aged 6 years and older with epilepsy;
• Myoclonic seizures in adults and children aged 12 years and older with juvenile myoclonic epilepsy;
• Primary generalized tonic-clonic seizures in adults and children 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 trial data in adult patients indicate that levetiracetam has no effect on other 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 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 concurrently administered carbamazepine and valproate. However, data indicate that the clearance of levetiracetam is 20% higher in children taking enzyme-inducing anticonvulsants. Dose adjustment is not required.

Probenecid.

Probenecid (500 mg four times daily), a drug that blocks renal tubular secretion, inhibits the renal clearance of the main metabolite but not of levetiracetam itself. However, concentrations of this metabolite remain low. Other drugs eliminated by active tubular secretion are also expected to reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid has not been studied, and the effect of levetiracetam on other actively secreted drugs, such as nonsteroidal anti-inflammatory drugs and sulfonamides, is unknown.

Methotrexate.

There have been reports that concomitant administration of levetiracetam and methotrexate reduces the clearance of methotrexate, 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 (LH 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, in turn, do not affect the pharmacokinetics of levetiracetam when administered concomitantly.

Laxatives.

In isolated 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.

Antacids.

There are no data on the effect of antacid agents on the absorption of levetiracetam.

Food and alcohol.

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

Special precautions for use.

Discontinuation of treatment.

If discontinuation of the medication is necessary, it is recommended to taper off gradually (e.g., for adults and adolescents with body weight ≥50 kg – reduce the dose by 500 mg twice daily every 2–4 weeks; for children and adolescents with body weight <50 kg – reduce the dose by not more than 10 mg/kg twice daily every 2 weeks).

Renal impairment.

Patients with renal impairment may require dose adjustment of levetiracetam. Patients with severe hepatic dysfunction should have renal function assessed before determining the drug dosage (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.

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 marked weakness, fever, recurrent infections, or bleeding disorders (see section "Adverse reactions").

Suicidality.

Cases of suicide, suicide attempts, suicidal ideation, and suicidal behavior 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 behavior. The mechanism of this risk is not understood. Due to this risk, patients should be monitored for signs of depression, suicidal ideation, and behavior, and treatment should be adjusted if necessary. Patients (or their caregivers) should be advised to report any symptoms of depression, suicidal thoughts, or behavior to their physician.

Pediatric population.

The tablet formulation is not suitable for use in 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.

Pregnancy.

Animal studies indicate reproductive toxicity. Analysis of data from pregnancy registries involving approximately 1000 women treated with levetiracetam monotherapy during the first trimester did not confirm a significant increase in the risk of major congenital malformations, although teratogenic risk cannot be completely excluded. The use of multiple antiepileptic drugs may potentially increase the risk of fetal malformations compared to monotherapy. Levetiracetam should not be used during pregnancy unless absolutely necessary, and should also be avoided in women of childbearing potential who are not using contraception. Physiological changes during pregnancy may alter levetiracetam concentrations. Decreased plasma levels of levetiracetam have been observed during pregnancy, most pronounced in the third trimester (up to 60% lower than pre-pregnancy baseline). Adequate clinical monitoring of pregnant women receiving levetiracetam is essential. Discontinuation of antiepileptic drugs may lead to worsening of the underlying condition, which could harm both mother and fetus.

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.

Effect on fertility.

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

Ability to drive and use machines.

Levetiracetam has a minor or moderate effect on the ability to drive or operate machinery. Due to possible individual sensitivity, some patients may experience somnolence, dizziness, and other central nervous system-related symptoms, particularly at the beginning of treatment or during dose escalation. Therefore, such patients should exercise caution when engaging in activities requiring high concentration, such as driving a car or operating machinery. Patients are advised to refrain from driving 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, regardless of food intake. The daily dose should be divided into 2 equal administrations.

Monotherapy

Adults and children aged 16 years and older

Monotherapy in adults and children aged 16 years and older should be initiated at the recommended dose of 500 mg/day (250 mg twice daily), with subsequent dose escalation to 1000 mg/day (500 mg twice daily) after 2 weeks. The dose may be increased by 500 mg/day (250 mg twice daily) every 2 weeks, depending on clinical response. The maximum daily dose is 3000 mg/day (1500 mg twice daily).

Children under 16 years of age

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

Data are lacking.

Adjunctive Therapy

Adjunctive therapy in adults (≥18 years) and children aged 12 to 17 years with body weight ≥50 kg

In adults and children aged 12 years and older with body weight greater than 50 kg, treatment should be initiated at a dose of 1000 mg/day (500 mg twice daily). This is the initial dose prescribed 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 by 1000 mg/day (500 mg twice daily) may be made every 2–4 weeks.

Adjunctive therapy in children aged 6 to 17 years with body weight less than 50 kg

The physician must select the most appropriate dosage form, route of administration, and number of doses based on body weight and required dose.

Adjunctive therapy in children aged 6 years and older should be initiated at a dose of 10 mg/kg twice daily. Depending on clinical response and tolerability, the dose may be increased up to 30 mg/kg twice daily. The dose should not be increased or decreased by more than 10 mg/kg twice daily every 2 weeks. The lowest effective dose should be used.

Treatment in children with body weight of 25 kg or less should preferably be initiated with levetiracetam oral solution 100 mg/mL.

In children with body weight exceeding 50 kg, dosing should follow the adult regimen.

Adjunctive therapy in infants aged 1 to 6 months

Infants should be administered the drug in the form of oral solution.

Special Patient Populations

Elderly patients (aged 65 years and older)

Dose adjustment is recommended in elderly patients with impaired renal function (see section "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, 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 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 in renal impairment 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) 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 associated with renal function. This recommendation is based on a study conducted in adult patients with impaired renal function.

For children, creatinine clearance (CC) in ml/min/1.73 m² can be calculated from 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 (under 6 years of age) 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, levetiracetam in other pharmaceutical forms should be used.

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

(3) After dialysis, an additional dose of 5–10 mg/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 required dose.

The tablet form of the drug is not recommended for use in children under 6 years of age. In addition, 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. Age restrictions related to the type of epilepsy are provided in the section "Indications". Children under 6 years of age or children weighing less than 25 kg should start treatment with levetiracetam oral solution.

Children

The tablet form of the drug is not recommended for use in children under 6 years of age. Levetiracetam oral solution should be used in children from 1 month of age up to 6 years of age.

Monotherapy

Safety and efficacy of the drug as monotherapy in children under 16 years of age have not been established.

Overdose

Symptoms

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

Treatment

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

Adverse Reactions

Infections and infestations: infections, nasopharyngitis.

General disorders: asthenia, increased fatigue.

Nervous system disorders: somnolence, headache, convulsions, impaired balance, dizziness, lethargy, tremor, amnesia, memory impairment, ataxia, paresthesia, attention disturbances, hyperkinesia, dyskinesia, choreoathetosis.

Blood and lymphatic system disorders: thrombocytopenia, leukopenia, neutropenia, pancytopenia, agranulocytosis.

Immune system disorders: drug reaction with eosinophilia and systemic symptoms (DRESS), hypersensitivity (including angioedema and anaphylaxis).

Gastrointestinal disorders: abdominal pain, diarrhea, dyspepsia, nausea, vomiting, pancreatitis.

Psychiatric disorders: depression, hostility/aggression, anxiety, insomnia, nervousness/irritability, suicide attempts, suicidal ideation, psychotic disorders, abnormal behavior, hallucinations, anger, confusion, panic attacks, affective lability/mood changes, agitation, personality disorders, thinking abnormalities.

Metabolism and nutrition disorders: anorexia, increased or decreased body weight, hyponatremia.

Ear and labyrinth disorders: vertigo.

Eye disorders: diplopia, blurred vision.

Musculoskeletal and connective tissue disorders: myalgia, muscle weakness. Rhabdomyolysis and elevated blood creatine phosphokinase levels (higher incidence observed in Japanese patients compared to non-Japanese patients).

Injury, poisoning and procedural complications: injuries.

Respiratory system disorders: cough.

Skin and subcutaneous tissue disorders: rash, eczema, pruritus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, alopecia (in several cases of alopecia, recovery of hair growth was observed after discontinuation of levetiracetam).

Hepatobiliary disorders: abnormal liver function tests, hepatitis, hepatic failure.

Renal and urinary disorders: acute kidney injury.

General disorders and administration site conditions: asthenia, increased fatigue.

Cases of encephalopathy have been rarely reported following levetiracetam administration. These adverse effects typically occurred early in treatment (within days to months) and were reversible upon discontinuation of therapy.

Description of selected adverse reactions

The risk of anorexia increases when levetiracetam is used concomitantly with topiramate. In cases of alopecia, recovery of hair growth has been observed in some patients after discontinuation of levetiracetam.

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

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, with 60 of these patients participating in placebo-controlled trials. Among patients aged 4–16 years, a total of 645 patients received levetiracetam treatment in placebo-controlled and open-label add-on studies, with 233 of these patients participating in placebo-controlled trials. Data from both age groups were supplemented with post-marketing safety data.

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

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 aged 4–16 years, vomiting (very common, 11.2%), agitation (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. In 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 conducted to demonstrate non-inferiority of levetiracetam compared to active control, the effects of levetiracetam on cognitive and neuropsychological parameters were evaluated in children aged 4–16 years with partial seizures. The drug did not differ from placebo (was not less effective) in terms of change from baseline in attention and memory as measured by the Leiter-R scale and total memory score in the per-protocol population. Behavioral and emotional function outcomes indicated increased aggression in patients treated with levetiracetam, as assessed systematically and standardized using validated tools (CBCL – Achenbach Child Behavior Checklist). However, in patients receiving levetiracetam during a long-term open-label follow-up study, no overall worsening of behavioral and emotional functions was observed on average; specifically, aggression scores did not worsen compared to baseline.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug 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 through the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 3 or 5 blisters per cardboard box.

Prescription category. Prescription only.

Manufacturer.

1. Sun Pharmaceutical Industries Ltd.
2. Sun Pharma Laboratories Limited

Manufacturer's address and site of operations.

1. Survey No. 214, Plot No. 20, Gavt. Ind. Area, Phase II, Piparia, Silvassa – 396230, U.T. Dadra and Nagar Haveli, India.
2. 6-9, EPIP, Katra, Barie Brahmana, Jammu - 181133, Jammu and Kashmir, India.