Levetiracetam asino
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Levetiracetam Acino (Levetiracetam Acino)
Composition:
Active substance: levetiracetam;
1 tablet contains 250 mg or 500 mg of levetiracetam;
Excipients: microcrystalline cellulose type 101, sodium croscarmellose, colloidal anhydrous silicon dioxide, povidone, microcrystalline cellulose type 102, magnesium stearate;
Coating:
250 mg film-coated tablets: Opadry® II Blue coating substance [polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171), indigo carmine (E 132)].
500 mg film-coated tablets: Opadry® II White coating substance [polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171)].
Pharmaceutical form. Film-coated tablets.
Main physico-chemical properties:
250 mg film-coated tablets: blue, film-coated, round, biconvex tablets with a score line on one side.
500 mg film-coated tablets: white, film-coated, round, biconvex tablets with a score line on one side.
Pharmacotherapeutic group. Antiepileptic agents. Levetiracetam.
ATC code N03A X14.
Pharmacological properties.
Pharmacodynamics.
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine-acetamide) that differs chemically from known antiepileptic medicinal products.
Mechanism of action
The mechanism of action of levetiracetam is not fully understood. Based on in vitro and in vivo studies, it is presumed that levetiracetam does not alter the basic characteristics of nerve cells or normal neurotransmission. In vitro studies have shown that levetiracetam affects intraneuronal Ca2+ levels by partially inhibiting Ca2+ influx through N-type Ca2+ channels and reducing Ca2+ release from intraneuronal stores. It also partially counteracts the inhibition of GABA- and glycine-regulated currents induced by zinc and β-carbolines. Furthermore, in vitro studies have demonstrated that levetiracetam binds to specific sites in brain tissues of rodents. The binding site is synaptic vesicle protein 2A (SV2A), which is involved in vesicle fusion and neurotransmitter release. The affinity (in rank order) of levetiracetam and its corresponding analogs for synaptic vesicle protein 2A correlated with the potency of their anticonvulsant effects in models of audiogenic epilepsy in mice. These findings suggest that the interaction between levetiracetam and synaptic vesicle protein 2A may partially explain the mechanism of its antiepileptic action.
Pharmacodynamic effects
Levetiracetam prevents the occurrence of seizures, as demonstrated in a broad range of animal models of partial and primarily generalized seizures, without causing proconvulsant effects. The primary metabolite of levetiracetam is inactive.
In humans, the drug's activity has been confirmed for both partial and generalized epileptic seizures (epileptiform discharges / photoparoxysmal response), indicating a broad pharmacological profile of levetiracetam.
Pharmacokinetics.
Levetiracetam is characterized by high solubility and permeability. Its pharmacokinetics are linear and characterized by low inter- and intrasubject variability. After repeated administration, the drug's clearance does not change. No influence of gender, race, or circadian rhythm on levetiracetam 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 of plasma levels of levetiracetam is not necessary.
In adults and children, a significant 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 administration of oral solution).
Adults and adolescents
Absorption
Levetiracetam is rapidly absorbed after oral administration. Absolute oral bioavailability is approximately 100%. Peak plasma concentration (Cmax) is reached within 1.3 hours after drug intake. Steady-state is achieved within 2 days of twice-daily administration. Peak concentrations (Cmax) are typically 31 and 43 µg/mL after a single 1000 mg dose and repeated 1000 mg twice daily, respectively. The extent of absorption is independent of dose and is not altered by food intake.
Distribution
There are no data on drug distribution in human tissues. Neither levetiracetam nor its primary metabolite significantly bind to plasma proteins (<10%). The volume of distribution of levetiracetam ranges from 0.5 to 0.7 L/kg, approximately equal to the total body water volume.
Metabolism
Levetiracetam metabolism 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 a wide range of tissues, including blood cells. The metabolite ucb L057 is pharmacologically inactive.
Two minor metabolites have also been identified: one formed by hydroxylation of the pyrrolidone ring (1.6% of dose), and the other by opening of the pyrrolidone ring (0.9% of dose).
Other undefined 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 have shown 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 not expected in vivo. Therefore, interaction of levetiracetam with other substances is unlikely.
Elimination
The elimination half-life of the drug from plasma in adults is 7±1 hours and does not depend on 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 glomerular filtration of levetiracetam followed by tubular reabsorption. In addition to glomerular filtration, the primary metabolite of levetiracetam is also excreted via active tubular secretion. Elimination of levetiracetam correlates with creatinine clearance.
Elderly patients
In elderly patients, elimination half-life increases by approximately 40% (10–11 hours). This is related to impaired renal function in this population (see section "Dosage and administration").
Patients with 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 for patients with moderate to severe renal impairment according to creatinine clearance (see section "Dosage and administration").
In patients with anuria in end-stage renal disease, the half-life of levetiracetam 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.
Patients with hepatic impairment
Levetiracetam clearance is not altered in patients with mild to moderate hepatic impairment. In most patients with severe hepatic impairment, levetiracetam clearance is reduced by more than 50% due to concomitant renal impairment (see section "Dosage and administration").
Pediatric population
Children aged 4–12 years
After administration of 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 (4–12 years), levetiracetam was rapidly absorbed. Peak plasma concentrations were reached within 0.5–1 hour after dosing. Peak concentrations and area under the concentration-time curve increased linearly and were dose-dependent. The elimination half-life was approximately 5 hours; apparent total clearance was 1.1 mL/min/kg.
Clinical Characteristics
Indications
Monotherapy (first-line treatment) for the treatment of:
- Partial-onset seizures with or without secondary generalization in adults and adolescents aged 16 years and older who have newly diagnosed epilepsy.
As adjunctive therapy in the treatment of:
- Partial-onset seizures with or without secondary generalization in adults, 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 derivatives of pyrrolidone, as well as to any excipients of the medicinal product.
Interaction with other medicinal products and other forms of interaction
Antiepileptic drugs
Pre-registration clinical trial 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 assessment of pharmacokinetic interactions in children and adolescents with epilepsy (aged 4 to 17 years) confirmed that adjunctive therapy with oral levetiracetam did not affect the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data indicate that the clearance of levetiracetam is 20% higher in children taking enzyme-inducing antiepileptic drugs. Dose adjustment is not required.
Probenecid
Probenecid (500 mg four times daily)—a drug that blocks renal tubular secretion—reduces the renal clearance of the main metabolite but not of levetiracetam itself. However, concentrations of this metabolite remain low.
Methotrexate
There have been reports that concomitant administration of levetiracetam and methotrexate reduces the clearance of methotrexate, leading to increased and/or 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 (levels of luteinizing hormone and progesterone) remained unchanged. Levetiracetam at a daily dose of 2000 mg does not alter the pharmacokinetics of digoxin and warfarin; prothrombin time values remained unchanged. Digoxin, oral contraceptives, and warfarin do not affect the pharmacokinetics of levetiracetam when co-administered.
Laxatives
In isolated cases, reduced efficacy of levetiracetam has been reported when co-administered with the osmotic laxative macrogol and 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 levetiracetam absorption is not affected by food intake, although the rate of absorption is slightly reduced when taken with food. There are no data available on the interaction between levetiracetam and alcohol.
Special precautions for use
Renal impairment
Patients with renal impairment may require dose adjustment of levetiracetam. Patients with severe hepatic impairment are recommended to undergo renal function assessment before determining the dosage regimen (see section "Dosage and administration").
Acute kidney injury
Acute kidney injury has been reported very rarely with levetiracetam use, with onset ranging from several days to several months.
Blood count
Rare cases of blood cell count reductions (neutropenia, agranulocytosis, leukopenia, thrombocytopenia, and pancytopenia) have been reported in association with levetiracetam use, typically at the beginning of treatment. A complete blood count is recommended in patients presenting with significant weakness, fever, recurrent infections, or bleeding disorders (see section "Adverse reactions").
Suicidal behaviour
Suicide attempts, suicidal ideation, and suicidal behaviour have been observed in patients treated with antiepileptic drugs (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs 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, suicidal thoughts, or behavioural changes, and treatment should be adjusted if necessary. Patients (and their caregivers) should be advised to report any symptoms of depression, 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 emergence of psychiatric disorders indicating significant mood and/or personality changes. If such behaviour occurs, dose adjustment or gradual discontinuation of treatment is recommended. For instructions on discontinuation, see section "Dosage and administration".
Exacerbation of seizures
As with other antiepileptic drugs, levetiracetam may rarely increase the frequency or severity of seizures. This paradoxical effect has most often been reported within the first month after starting levetiracetam or during dose escalation. This effect was reversible upon discontinuation or dose reduction of the drug. Patients should be advised to seek immediate medical advice if seizure exacerbation occurs.
In patients with epilepsy associated with mutations in the alpha subunit 8 of the voltage-gated sodium channel (SCN8A), lack of efficacy or worsening of seizures has been reported.
QT interval prolongation on electrocardiogram (ECG)
Rare cases of QT interval prolongation on ECG have been reported during post-marketing surveillance. Therefore, levetiracetam should be used with caution in patients with QT prolongation, in patients taking concomitant medications affecting 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 do not indicate any effect of levetiracetam on children's development or sexual maturation. However, the long-term impact of the drug on learning ability, intelligence, development, endocrine functions, sexual maturation, and reproductive function in children remains unknown.
The medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".
Use during pregnancy or breastfeeding
Women of childbearing potential
Special 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 drugs, abrupt discontinuation of levetiracetam should be avoided, as this may lead to seizures, 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 compared to monotherapy, depending on the drug combination.
Pregnancy
A large amount of post-marketing data from pregnant women using levetiracetam (over 1800 women, including 1500 women exposed 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, results from epidemiological studies (approximately 100 children) do not indicate an increased risk of neurodevelopmental disorders or delays. Levetiracetam may be used during pregnancy if, after careful 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 baseline concentrations). Adequate clinical monitoring should be ensured for pregnant women receiving levetiracetam.
Breastfeeding
Levetiracetam passes into human breast milk. Therefore, breastfeeding is not recommended during treatment with levetiracetam. However, if levetiracetam is required during breastfeeding, the benefits and risks of treatment should be weighed against the importance of breastfeeding.
Effects on fertility
No effects of levetiracetam on fertility were 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 to moderate influence on the ability to drive or operate machinery. Due to possible individual sensitivity, some patients may experience somnolence or other central nervous system-related symptoms, particularly at the beginning of treatment or during dose escalation. Therefore, such patients should exercise caution when engaging in activities requiring increased attention, such as driving or operating machinery. Patients are advised to refrain from driving or operating machinery until it is established that their ability to perform such activities is not impaired.
Method of Administration and Dosage
Tablets should be taken orally, swallowing 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 specified below.
All Indications
Adults (≥ 18 years) and adolescents (12–17 years) with body weight of 50 kg or more
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 picture and drug tolerability, the daily dose may be increased up to a maximum of 1500 mg twice daily. The dose may be adjusted by 250 mg or 500 mg twice daily every 2–4 weeks.
Children aged 6 years and older and adolescents (12–17 years) with body weight less than 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 drug 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.
Use the table below for dose adjustment in adults.
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 over 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 over 50 kg
| Renal impairment severity |
Creatinine clearance (mL/min/1.73 m2) |
Dosing regimen |
| Normal renal function |
> 80 |
500 to 1500 mg twice daily |
| Mild |
50−79 |
500 to 1000 mg twice daily |
| Moderate |
30−49 |
250 to 750 mg twice daily |
| Severe |
< 30 |
250 to 500 mg twice daily |
| End-stage (patients undergoing dialysis(1)) |
- |
500 to 1000 mg once daily(2) |
(1) On the first day of treatment with levetiracetam, a loading dose of 750 mg is recommended.
(2) An additional dose of 250–500 mg is recommended after dialysis.
For children with renal impairment, the dose of levetiracetam should be adjusted according to renal function, as levetiracetam clearance is related to renal function. This recommendation is based on a study 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):
 
| Renal impairment severity |
Creatinine clearance (mL/min/1.73 m²) |
Children aged 6 years and older and adolescents with body weight less than 50 kg(1) |
| Normal renal function |
> 80 |
10−30 mg/kg (0.10−0.30 mL/kg) twice daily |
| Mild impairment |
50−79 |
10−20 mg/kg (0.10−0.20 mL/kg) twice daily |
| Moderate impairment |
30−49 |
5−15 mg/kg (0.05−0.15 mL/kg) twice daily |
| Severe impairment |
< 30 |
5−10 mg/kg (0.05−0.10 mL/kg) twice daily |
| End-stage (patients on dialysis) |
- |
10−20 mg/kg (0.10−0.20 mL/kg) once daily (2)(3) |
(1) For doses up to 250 mg, for doses not multiples of 250 mg when the recommended dosage cannot be achieved by taking multiple tablets, and for patients unable to swallow tablets, Leviceptam 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 recommended daily maintenance dose should be reduced by 50%.
Children
The physician should select the most appropriate dosage form, strength, and formulation based on age, body weight, and calculated dose.
The tablet formulation is not recommended for children under 6 years of age or for patients unable to swallow tablets. For these patient groups, Leviceptam oral solution is preferred. 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 up to 250 mg. In all the above cases, treatment should be initiated with Leviceptam oral solution.
Monotherapy
The safety and efficacy of Levetiracetam Asino as monotherapy in children and adolescents under 16 years of age have not been established. Data are lacking.
Adolescents (16–17 years of age) with body weight ≥ 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) with body weight ≥ 50 kg».
Adjunctive therapy in children aged 6 years and older and adolescents (12–17 years) with body weight < 50 kg
Infants and children under 6 years of age should preferably be treated with Leviceptam oral solution.
Leviceptam oral solution should be used in children aged 6 years and older when dosing is up to 250 mg, for doses not multiples of 250 mg when the recommended dosage cannot be achieved by taking multiple 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 with a body weight of 25 kg should be 250 mg twice daily; the maximum dose is 750 mg twice daily.
Children with body weight above 50 kg should receive dosing according to the adult regimen for all indications.
See section above «Adults (≥ 18 years) and adolescents (12–17 years) with body weight ≥ 50 kg» for all indications.
Adjunctive therapy in infants aged 1 to 6 months
Infants should be treated with the oral solution formulation.
Children
The tablet formulation is not recommended for children under 6 years of age. Infants aged 1 month and children under 6 years of age should be treated with Leviceptam oral solution.
Overdose
Symptoms
Symptoms observed in levetiracetam overdose include somnolence, agitation, aggression, respiratory depression, decreased level of consciousness, and coma.
Treatment
In acute overdose, gastric lavage or induction of emesis should be performed. There is no specific antidote for levetiracetam. Symptomatic treatment should be administered as needed, including hemodialysis (up to 60% of levetiracetam and 74% of the main metabolite can be removed).
Adverse reactions
The most commonly reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue, and dizziness. The adverse reaction profile described below is based on a pooled analysis of data from placebo-controlled clinical trials across all indications, involving a total of 3416 patients who received levetiracetam. These data are supplemented by the use of levetiracetam in appropriate extended open-label studies and post-marketing experience. The safety profile of levetiracetam is generally similar across different age groups (adults and children) when used for 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 below 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).
Infections and infestations: very common – nasopharyngitis; rare – infections.
Blood and lymphatic system disorders: uncommon – thrombocytopenia, leukopenia; rare – neutropenia, pancytopenia, agranulocytosis.
Immune system disorders: rare – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), hypersensitivity (including angioedema and anaphylaxis).
Mental and behavioural disorders: common – depression, hostility, aggression, anxiety, insomnia, irritability, nervousness; uncommon – suicide attempts and suicidal ideation, psychotic disorders, abnormal behaviour, hallucinations, anger, confusion, panic attacks, emotional lability/mood changes, agitation; rare – suicide, personality disorders, abnormal thoughts, delirium; very rare – obsessive-compulsive disorder**.
Nervous system disorders: very common – somnolence, headache; common – seizures, impaired balance, dizziness, lethargy, tremor; uncommon – amnesia, memory impairment, ataxia, coordination difficulties, paraesthesia, attention disorders; rare – hyperkinesia, choreoathetosis, dyskinesia, gait disturbance, encephalopathy, increased seizures, neuroleptic malignant syndrome*.
Eye disorders: uncommon – diplopia, blurred vision.
Ear and labyrinth disorders: common – vertigo.
Cardiac disorders: rare – QT interval prolongation on ECG.
Respiratory, thoracic and mediastinal disorders: common – cough.
Gastrointestinal disorders: common – abdominal pain, diarrhoea, dyspepsia, nausea, vomiting; rare – pancreatitis.
Hepatobiliary disorders: uncommon – liver function test abnormalities; rare – hepatitis, hepatic failure.
Renal and urinary disorders: rare – acute kidney injury.
Skin and subcutaneous tissue disorders: common – rash; uncommon – eczema, pruritus, alopecia; rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.
Musculoskeletal and connective tissue disorders: uncommon – myalgia, muscle weakness; rare – rhabdomyolysis and elevated creatine phosphokinase in blood*.
General disorders: common – asthenia, fatigue.
Injury, poisoning and procedural complications: uncommon – injuries.
* The frequency of occurrence is significantly higher in Japanese patients compared to non-Japanese patients.
** Very rare cases of development of obsessive-compulsive disorders (OCD) have been observed in patients with a history of OCD or psychiatric disorders during post-marketing surveillance.
Description of selected adverse reactions
The risk of anorexia increases when levetiracetam is used concomitantly with topiramate.
In some cases of alopecia, hair regrowth occurred after discontinuation of levetiracetam.
In cases of pancytopenia, bone marrow suppression was observed in some instances.
Cases of encephalopathy were usually observed early in treatment (within days to months) and were reversible upon discontinuation of therapy.
Children
Among patients aged 1 month to 4 years, a total of 190 patients received levetiracetam treatment in placebo-controlled and open-label extension studies, of which 60 were enrolled in placebo-controlled trials. Among patients aged 4–16 years, a total of 645 patients received levetiracetam treatment in placebo-controlled and open-label extension studies, of which 233 participated in placebo-controlled trials. For both age groups, these data are supplemented by post-marketing experience.
Additionally, in a post-marketing safety study, 101 infants under 12 months of age received treatment. No new safety data were obtained regarding the use of levetiracetam 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 data in children from placebo-controlled clinical trials were consistent with the safety profile in adults, except for behavioural and psychiatric adverse reactions, which occurred more frequently in children than in adults. In children and adolescents 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 behaviour (common, 5.6%), and lethargy (common, 3.9%) occurred more frequently than in other age groups or the overall safety profile. In infants and children aged 1 month to 4 years, irritability (very common, 11.7%) and coordination difficulties (common, 3.3%) occurred more frequently than in other age groups or the overall safety profile.
In a double-blind, placebo-controlled safety study in children conducted to demonstrate non-inferiority of the drug compared to placebo, the effects of levetiracetam on cognitive and neuropsychological parameters were evaluated in children aged 4–16 years with partial seizures. Results showed that levetiracetam did not differ from placebo 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. However, behavioural and emotional function assessments indicated increased aggressive behaviour in patients treated with levetiracetam, as systematically and standardly assessed using validated tools (CBCL – Achenbach Child Behavior Checklist). Nevertheless, in patients receiving levetiracetam during long-term open-label follow-up studies, no overall worsening of behavioural and emotional functions was observed, and aggressive behaviour scores did not deteriorate compared to baseline.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after medicine registration is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
In case of adverse reactions or questions regarding the safety and efficacy of the medicine, please contact the Pharmacovigilance Department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, tel/fax: +38 044 281 2333.
Shelf life. 2 years.
Storage conditions. Store in a place inaccessible to children, in the original packaging at a temperature not exceeding 25 °C.
Packaging. 10 tablets per blister; 3 or 6 blisters per carton.
Prescription status. Prescription only.
Manufacturer. LLC "Pharma Start".
Manufacturer's address and location of business activity.
8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.