Levvenium

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LEVENIUM (LEVENIUM)

Composition:

Active substance: levetiracetam;

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

Excipients:

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

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

750 mg tablets: maize starch, povidone, sodium croscarmellose, anhydrous colloidal 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);

1000 mg tablets: maize starch, povidone, sodium croscarmellose, anhydrous colloidal 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:

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

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

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

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

Pharmacotherapeutic group.

Antiepileptic agents. Levetiracetam. ATC code N03AX14.

Pharmacological Properties

Pharmacodynamics

Levetiracetam is a pyrrolidone derivative (the 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 is established that its mechanism differs from that of known antiepileptic agents. Based on in vitro and in vivo studies, levetiracetam is presumed 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.

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

In humans, the 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, 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 concentrations 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 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 dose-independent and not affected by food.

Distribution

There are no data on tissue distribution of the drug in humans. Neither levetiracetam nor its primary 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 main metabolic pathway (24% of dose) is enzymatic hydrolysis of the acetamide group. Hepatic cytochrome P450 isoenzymes are not involved in the formation of the primary 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 formed by hydroxylation of the pyrrolidone ring (1.6% of dose), and another 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 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 conjugation of CYP1A1/2, SULT1E1, or UGT1A1. At high concentrations (680 µg/mL), levetiracetam caused weak induction of CYP2B6 and CYP3A4, but this effect was not biologically significant at concentrations comparable to Cmax after repeated 1500 mg twice daily dosing. In vitro and in vivo data on interactions with oral contraceptives, digoxin, and warfarin suggest that significant enzyme induction is not expected under in vivo conditions. 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 is excreted within 48 hours). Only 0.3% of the dose is excreted in feces.

Cumulative urinary excretion of levetiracetam and its primary metabolite within the first 48 hours is 66% and 24% of the dose, respectively. Renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 mL/min/kg, respectively, indicating that levetiracetam is eliminated by glomerular filtration with subsequent tubular reabsorption, while 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, 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 primary metabolite correlates with creatinine clearance. Therefore, dose adjustment of the maintenance daily dose of levetiracetam is recommended in patients with moderate and severe renal impairment according to 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 standard 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 dysfunction, creatinine clearance may not fully reflect the severity of renal impairment. 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 (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 epilepsy patients. After repeated oral administration (20–60 mg/kg/day) in children with epilepsy (4–12 years), levetiracetam was rapidly absorbed. Peak plasma concentrations were reached within 0.5–1 hour after dosing. Peak concentrations and area under the concentration-time curve increased linearly and were dose-dependent. 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, as well as to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Antiepileptic drugs

Pre-registration data from clinical studies in adult patients indicate that levetiracetam does not affect other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone), and these drugs, in turn, do not affect the pharmacokinetics of levetiracetam.

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

A retrospective 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—reduces the renal clearance of the main metabolite, but not of levetiracetam itself. However, concentrations of this metabolite remain low. Other drugs eliminated via 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 use of levetiracetam and methotrexate reduces the clearance of methotrexate, 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 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) remained unchanged. Levetiracetam at a daily dose of 2000 mg does not alter the pharmacokinetics of digoxin and warfarin; prothrombin time values remained unchanged. Conversely, digoxin, oral contraceptives, and warfarin do not affect the pharmacokinetics of levetiracetam when administered concomitantly.

Laxatives

In isolated cases, reduced efficacy of levetiracetam has been reported when administered concomitantly with the osmotic laxative macrogol taken orally. 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 medications 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 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 are recommended to undergo assessment of renal function before determining the dose of the drug (see section "Dosage and administration").

Acute kidney injury

Acute kidney injury has very rarely been reported with the use of levetiracetam, with onset ranging from several days to several months.

Complete blood count

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

Suicidal behaviour

Suicide, suicide attempts, suicidal thoughts, and suicidal behaviour have been observed in patients receiving antiepileptic drugs (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 of this risk is not known. Due to this risk, patients should be monitored for the emergence of depression and/or suicidal thoughts and behaviour, and treatment should be adjusted as necessary. Patients (and their caregivers) should be advised to report any symptoms of depression and/or suicidal thoughts 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 development of psychiatric signs indicating significant mood and/or personality changes. If such behaviour occurs, it is recommended to adjust the treatment or gradually discontinue the drug. For information on discontinuation, see the section "Dosage and administration".

Worsening of seizures

As with other antiepileptic drugs, levetiracetam may rarely increase the frequency or severity of seizures. This paradoxical effect has most frequently been reported during the first month after initiation of levetiracetam or during dose escalation. This effect was reversible upon discontinuation of the drug or dose reduction. Patients should be advised to seek immediate medical advice if their epilepsy worsens.

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 taking concomitant medications that affect the QT interval, and in patients with relevant 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 and sexual maturation. However, the long-term impact on learning ability, intelligence, development, endocrine functions, sexual maturation, and reproductive function in children remains unknown.

The medicinal product contains the colouring agent Sunset Yellow, which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Women of childbearing potential

Special recommendations 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 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 drugs may be associated with a higher risk of congenital malformations than 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 levetiracetam monotherapy in utero. However, existing epidemiological studies (approximately 100 children) do not indicate an increased risk of neurodevelopmental disorders or developmental delay. Levetiracetam may be used during pregnancy if, after careful evaluation, 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 pre-pregnancy concentration). Adequate clinical monitoring should be ensured for pregnant women receiving levetiracetam.

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 the lack of available clinical data.

Ability to affect 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, dizziness, and other central nervous system-related symptoms, particularly at the beginning of treatment or during dose escalation. Therefore, such patients should exercise caution when engaging in activities requiring heightened attention, such as driving a car or operating machinery. Patients are advised to refrain from driving vehicles or 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 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 to 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 prescribed by the physician 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 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 to 17 years) with body weight < 50 kg

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

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 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 for 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 women).
72 × serum creatinine (mg/dL)

Then, adjust CrCl according to body surface area (BSA) as follows:

CrCl (mL/min)
CrCl (mL/min/1.73m²) = --------------------------- × 1.73.
BSA of patient (m²)

Dosing Regimen for Adults and Adolescents with Renal Impairment and Body Weight > 50 kg

Table 1

(1) On the first day of levetiracetam treatment, 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, since levetiracetam clearance 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, 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)

In children under 13 years of age and adolescent girls, ks = 0.55; in 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 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 daily maintenance dose should be reduced by 50%.

Children

The physician should select the most appropriate pharmaceutical form, dosage strength, and formulation based on the patient's 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 levetiracetam oral solution. Furthermore, 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 administering doses below 250 mg. In all the aforementioned cases, treatment should be initiated with the oral solution.

Monotherapy

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

Data are lacking.

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

For children aged 6 years and older, oral solution of levetiracetam should be used for dosing 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 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.

For children weighing more than 50 kg, dosing for all indications should follow the adult regimen.

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. Levetiracetam oral solution should be used in infants from 1 month of age and in children under 6 years of age.

Overdose

Symptoms

Symptoms observed in overdose include somnolence, agitation, aggression, respiratory depression, impaired 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

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 the 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 presented in decreasing order of 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

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

Description of selected adverse reactions.

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

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

Cases of encephalopathy were generally 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. Sixty of these 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. 233 of these patients received levetiracetam in placebo-controlled studies. For both age groups, these data are supplemented by post-marketing experience.

Additionally, 101 infants under 12 months of age were included in a post-marketing safety study of the drug. No new safety data on the use of levetiracetam 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 in children from placebo-controlled clinical trials were consistent with the safety profile of levetiracetam in adults, except for behavioral and psychiatric adverse reactions, which were more frequent in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), irritability (common, 3.4%), mood changes (common, 2.1%), affective lability (common, 1.7%), aggression (common, 8.2%), 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%) occurred more frequently than in other age groups or in the overall safety profile.

In a double-blind, placebo-controlled safety study in children conducted to demonstrate non-inferiority of the drug, the effect of levetiracetam on cognitive and neuropsychological parameters was evaluated in children aged 4 to 16 years with partial seizures. Levetiracetam did not differ from placebo (was not inferior) in 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 results indicated increased aggression in patients treated with levetiracetam, as systematically and consistently assessed using validated tools (CBCL – Achenbach Child Behavior Checklist). However, in patients receiving levetiracetam in a long-term open-label follow-up study, no overall worsening of behavioral and emotional functions was observed on average, including aggression scores which did not worsen from baseline.

Reporting suspected adverse reactions

Reporting of adverse reactions after drug registration is important. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

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

Prescription status. Prescription only.

Manufacturer.

Sun Pharmaceutical Industries Ltd.

Manufacturer's address and location of operations.

Survey No. 214, Plot No. 20, Gavt. Indl. Area, Phase II, Piparia, Silvassa – 396230, U.T. Dadra and Nagar Haveli, India.