Instructions Levetiracetam Asino film-coated tablets 250 mg blister No. 30
Composition
active ingredient: levetiracetam;
1 tablet contains levetiracetam 250 mg or 500 mg;
excipients: microcrystalline cellulose type 101, croscarmellose sodium, colloidal anhydrous silicon dioxide, povidone, microcrystalline cellulose type 102, magnesium stearate;
shell:
film-coated tablets, 250 mg: coating agent Opadry® II Blue [polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171), indigo carmine (E 132)].
500 mg film-coated tablets: coating agent Opadry® II White [polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171)].
Dosage form
Film-coated tablets.
Main physicochemical properties:
Film-coated tablets, 250 mg: blue film-coated tablets, with a biconvex surface, round in shape, with a score on one side.
Film-coated tablets, 500 mg: white, biconvex, round, film-coated tablets with a score on one side.
Pharmacotherapeutic group
Antiepileptic drugs. Levetiracetam.
ATX code N03A X14.
Pharmacological properties
Pharmacodynamics.
The active substance levetiracetam is a pyrrolidone derivative (S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine-acetamide), which differs in chemical structure from known antiepileptic drugs.
Mechanism of action
The mechanism of action of levetiracetam is not well understood. Based on in vitro and in vivo studies, it is assumed that levetiracetam does not alter the basic characteristics of the nerve cell and normal neurotransmission. In vitro studies have shown that levetiracetam affects intracellular Ca2+ levels by partially inhibiting current through N-type Ca2+ channels and reducing the release of Ca2+ from intracellular depots. It also partially eliminates the inhibition of GABA- and glycine-gated currents caused by the action of zinc and β-carbolines. In addition, in vitro studies have shown that levetiracetam binds to specific sites in rodent brain tissue. The binding site is synaptic vesicle protein 2A, which is involved in vesicle fusion and neurotransmitter release. The affinity (ranked) of levetiracetam and its analogues for synaptic vesicle protein 2A correlated with their anticonvulsant potency in mouse models of audiogenic epilepsy. These results suggest that an interaction between levetiracetam and synaptic vesicle protein 2A may partially explain the mechanism of the drug's antiepileptic action.
Pharmacodynamic effects
Levetiracetam prevents the onset of seizures, as demonstrated in a wide range of animal models of partial and primary generalized seizures, without causing a proconvulsant effect. The main metabolite of levetiracetam is inactive.
In humans, the drug's activity has been confirmed against both partial and generalized epileptic seizures (epileptiform manifestations/photoparoxysmal response), indicating a broad spectrum of the pharmacological profile of levetiracetam.
Pharmacokinetics.
Levetiracetam is characterized by high solubility and permeability. The pharmacokinetics are linear and characterized by low inter- and intrasubject variability. After repeated administration of the drug, its clearance does not change. There was no evidence of the influence of gender, race or circadian rhythm on the pharmacokinetics of levetiracetam. Its pharmacokinetic profile was similar in healthy volunteers and patients with epilepsy.
Due to complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed in mg/kg body weight. Therefore, monitoring of levetiracetam plasma levels is not necessary.
In adults and children, a significant correlation was observed between saliva and plasma concentrations (saliva/plasma concentration ratios ranged from 1 to 1.7 after oral tablets and 4 hours after oral solution).
Adults and adolescents
Absorption
Levetiracetam is rapidly absorbed after oral administration. Absolute oral bioavailability is approximately 100%. Peak plasma concentrations (Cmax) are reached 1.3 hours after dosing. Steady state is reached after 2 days of twice daily dosing. Peak concentrations (Cmax) are typically 31 and 43 μg/mL after a single 1000 mg dose and a repeated 1000 mg dose twice daily, respectively. The extent of absorption is independent of dose and is not affected by food intake.
Distribution
There are no data on the distribution of the drug in human tissues. Neither levetiracetam nor its main metabolite is significantly bound to plasma proteins (
Metabolism
Two minor metabolites were also identified. One was formed by hydroxylation of the pyrrolidone ring (1.6% of the dose), the other by opening of the pyrrolidone ring (0.9% of the dose).
Other unidentified components accounted for only 0.6% of the dose.
No interconversion of enantiomers of levetiracetam or its major metabolite was observed in vivo.
In vitro studies have shown that levetiracetam and its major metabolite did not inhibit the activity of the major human hepatic cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyltransferases (UGT1A1 and UGT1A6) and epoxide hydroxylase. Levetiracetam also does not inhibit the glucuronidation of valproic acid in vitro.
In human hepatocyte culture, levetiracetam had little or no effect on CYP1A1/2, SULT1E1 or UGT1A1. Levetiracetam induced a weak induction of CYP2B6 and CYP3A4. In vitro and in vivo data on interactions with oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected in vivo. Therefore, interactions of levetiracetam with other substances are unlikely.
Breeding
The plasma elimination half-life in adults was 7±1 h and was independent of dose, route of administration, or repeated administration. The mean total clearance was 0.96 mL/min/kg.
The main amount of the drug, on average 95% of the dose, was excreted in the urine (approximately 93% of the dose was excreted within 48 hours). Only 0.3% of the dose was excreted in the feces.
The cumulative urinary excretion of levetiracetam and its major metabolite was 66% and 24% of the dose, respectively, in the first 48 hours. The 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. The major metabolite of levetiracetam is also eliminated by active tubular secretion in addition to glomerular filtration. The elimination of levetiracetam correlates with creatinine clearance.
Elderly patients
In elderly patients, the elimination half-life is increased by approximately 40% (10-11 hours). This is due to the deterioration of renal function in this population (see section "Method of administration and dosage").
Patients with renal impairment
The apparent total clearance of levetiracetam and its main metabolite correlates with creatinine clearance. Therefore, in patients with moderate to severe renal impairment, it is recommended to adjust the maintenance daily dose of levetiracetam according to creatinine clearance (see section 4.2).
In anuric patients with end-stage renal disease, the elimination half-life of levetiracetam was approximately 25 and 3.1 hours, respectively, between and during dialysis sessions. During a typical 4-hour dialysis session, 51% of levetiracetam was removed.
Patients with hepatic impairment
Levetiracetam clearance was not altered in patients with mild to moderate hepatic impairment. In most patients with severe hepatic impairment, levetiracetam clearance was reduced by more than 50% due to concomitant renal impairment (see section 4.2).
Pediatric population
Children aged 4−12 years
After a single dose (20 mg/kg) in epileptic children (6 to 12 years), the elimination half-life of levetiracetam was 6 hours. The apparent clearance, adjusted for body weight, was approximately 30% higher than in adult patients with epilepsy. After repeated oral administration (20-60 mg/kg/day) in epileptic children (4-12 years), levetiracetam was rapidly absorbed. Peak plasma concentrations were reached 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.
Indication
Monotherapy (first-choice drug) in the treatment of:
- partial seizures with or without secondary generalization in adults and adolescents aged 16 years and older with newly diagnosed epilepsy.
As an additional therapy in the treatment of:
- partial seizures with or without secondary generalization in adults, adolescents and children aged 6 years and over with epilepsy;
- myoclonic seizures in adults and adolescents aged 12 years and over with juvenile myoclonic epilepsy;
- primary generalized convulsive (tonic-clonic) seizures in adults and adolescents aged 12 years and older with idiopathic generalized epilepsy.
Contraindication
Hypersensitivity to levetiracetam or other pyrrolidone derivatives, as well as to any of the excipients of the drug.
Interaction with other medicinal products and other types of interactions
Antiepileptic drugs
Pre-marketing data from clinical studies in adult patients indicate that levetiracetam does not affect the serum concentrations of existing antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone), which in turn do not affect the pharmacokinetics 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 suggest that levetiracetam clearance is 20% higher in children taking enzyme-inducing antiepileptic drugs. No dose adjustment is required.
Probenecid
Probenecid (500 mg 4 times daily), a drug that blocks renal tubular secretion, inhibits renal clearance of the major metabolite, but not levetiracetam itself. However, concentrations of this metabolite remain low.
Methotrexate
Concomitant use of levetiracetam and methotrexate has been reported to reduce the clearance of methotrexate, leading to increased/prolonged blood concentrations of methotrexate to potentially toxic levels. Methotrexate and levetiracetam blood levels should be closely monitored in patients receiving both drugs concurrently.
Oral contraceptives and pharmacokinetic interactions with other drugs
Levetiracetam at a daily dose of 1000 mg did not alter the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone levels) were not changed. Levetiracetam at a daily dose of 2000 mg did not alter the pharmacokinetics of digoxin and warfarin; prothrombin time values remained unchanged. Digoxin, oral contraceptives and warfarin do not affect the pharmacokinetics of levetiracetam when administered simultaneously.
Laxatives
In isolated cases, reduced efficacy of levetiracetam has been reported when the osmotic laxative macrogol was used concomitantly with oral levetiracetam. Therefore, oral macrogol should not be taken within one hour before or one hour after taking levetiracetam.
Food and alcohol
The extent of absorption of levetiracetam is independent of food intake, but the rate of absorption is slightly reduced when taken with food. There are no data on the interaction of levetiracetam with alcohol.
Application features
Kidney failure
Patients with renal impairment may require dose adjustment of levetiracetam. In patients with severe hepatic impairment, it is recommended that renal function be assessed before dose adjustment (see section 4.2).
Acute kidney injury
The use of levetiracetam has been very rarely associated with acute kidney injury, the time to onset of which ranged from a few 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, usually at the start of treatment. Complete blood counts are recommended in patients who present with significant weakness, fever, recurrent infections or coagulation disorders (see section 4.8).
Suicide
Suicide, suicide attempts, suicidal thoughts and behaviour have been reported in patients treated with antiepileptic drugs (including levetiracetam). A meta-analysis of randomised placebo-controlled trials of antiepileptic drugs has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. In view of this risk, patients should be monitored for signs of depression, suicidal thoughts and behaviour and treatment should be adjusted as necessary. Patients (and their carers) should be advised to report any symptoms of depression, suicidal thoughts or behaviour to their doctor.
Unusual or aggressive behavior
Levetiracetam may cause psychotic symptoms and behavioral disturbances, including irritability and aggression. Patients taking levetiracetam should be monitored for signs of psychiatric disorders, such as significant changes in mood and/or personality. If such behaviour occurs, it is recommended to adjust the treatment or gradually discontinue it. If treatment discontinuation is necessary, see section "Method and dosage".
Worsening of attacks
As with other antiepileptic drugs, levetiracetam may occasionally increase the frequency or severity of seizures. This paradoxical effect has been most commonly reported within the first month of levetiracetam initiation or with dose increases. 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.
In patients with epilepsy associated with a mutation in the voltage-gated sodium channel alpha subunit 8 (SCN8A), lack of efficacy or worsening of seizures has been reported.
During post-marketing surveillance, rare cases of QT prolongation on ECG have been reported. Therefore, levetiracetam should be used with caution in patients with QT prolongation, in patients taking concomitant medications that affect the QT interval, and in patients with underlying cardiac disease or electrolyte imbalance.
Children
The drug in tablet form is not suitable for use in infants and children under 6 years of age.
Available data do not indicate any effects of levetiracetam on the development and sexual maturation of children. However, the long-term effects of the drug on learning ability, intelligence, development, endocrine function, sexual maturation and reproductive function in children remain unknown.
This medicine contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Women of reproductive age
Special advice should be given to women of childbearing potential. Levetiracetam treatment should be reconsidered if a woman is planning to become pregnant. As with all antiepileptic drugs, abrupt withdrawal of levetiracetam should be avoided as it may lead to seizures, which may have serious consequences for 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 birth defects than monotherapy, depending on the combination of drugs.
Pregnancy
A large amount of post-marketing data from pregnant women exposed to levetiracetam (more than 1800 women, including 1500 women exposed during the first trimester) does not indicate an increased risk of major birth defects. There are only limited data on the development of the nervous system in children exposed to levetiracetam monotherapy in utero. However, the results of epidemiological studies (approximately 100 children) do not indicate an increased risk of disorders or delays in the development of the nervous system. Levetiracetam can be used during pregnancy if, after careful assessment, it is considered clinically necessary. In such cases, the lowest effective dose is recommended.
Physiological changes during pregnancy may alter levetiracetam concentrations. Decreases in plasma levetiracetam concentrations have been observed during pregnancy. This decrease is most pronounced in the third trimester (up to 60% of pre-pregnancy baseline concentrations). Appropriate clinical monitoring of pregnant women receiving levetiracetam should be ensured.
Breast-feeding
Levetiracetam is excreted in human milk. Breastfeeding is therefore not recommended during treatment with levetiracetam. However, if levetiracetam is necessary during breast-feeding, the benefits and risks of treatment should be weighed against the importance of breast-feeding.
Impact on reproductive function
Levetiracetam has not been shown to have any effect on reproductive function in animal studies. The potential risk for humans is unknown as no clinical data are available.
Ability to influence reaction speed when driving vehicles or other mechanisms
Levetiracetam has minor or moderate influence on the ability to drive and use machines. Due to possible individual sensitivity, some patients may experience drowsiness or other symptoms related to the effects on the central nervous system, especially at the beginning of treatment or during dose increases. Therefore, such patients should be careful when engaging in activities that require increased concentration, such as driving or operating other machines. Patients are advised to refrain from driving or operating other machines until it is established that their ability to perform such activities is not impaired.
Method of administration and doses
The tablets should be taken orally with sufficient liquid, with or without food. When taken 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 over) and adjunctive therapy is the same and is listed below.
All indications
Adults (≥ 18 years) and adolescents (12 – 17 years) weighing 50 kg or more
The initial therapeutic dose is 500 mg twice daily. This is the initial dose prescribed on the first day of treatment. However, a lower initial dose of 250 mg twice daily may be used by the physician based on an assessment of the reduction in seizure frequency compared to potential side effects. This dose may be increased to 500 mg twice daily after 2 weeks.
Depending on the clinical picture and tolerability of the drug, the daily dose can be increased to a maximum of 1500 mg 2 times a day. The dose can be changed to 250 mg or 500 mg 2 times a day every 2-4 weeks.
Children aged 6 years and over and adolescents (12-17 years) weighing less than 50 kg
The physician should prescribe the most appropriate dosage form, dosage and release form based on body weight, age and dose. For information on dose adjustment based on body weight, see the Children section.
If it is necessary to discontinue the drug, it is recommended to do so gradually (for example: for adults and adolescents weighing 50 kg or more - reduce the dose by 500 mg 2 times a day every 2-4 weeks; for children and adolescents weighing less than 50 kg - reduce the single dose by no more than 10 mg/kg 2 times a day every 2 weeks).
Special patient groups
Elderly patients (65 years and older)
Dose adjustment is recommended for elderly patients with impaired renal function (see below “Renal failure”).
Kidney failure
The daily dose should be individually adjusted according to the state of renal function.
To adjust the dose for adults, use the table below.
To adjust the dose according to the table, it is necessary to determine the level of creatinine clearance (CC) in ml/min.
The creatinine clearance for adults and adolescents weighing more than 50 kg can be calculated based on serum creatinine concentration (mg/dL) using the formula:
[140 ─ age (years)] × body weight (kg)
CC (ml/min) = --------------------------------------------------------------× 0.85 (for women).
72 × serum creatinine (mg/dL)
The CK is then adjusted for body surface area (BSA) as shown below:
CC (ml/min)
CC (ml/min/1.73m2) = --------------------------- × 1.73.
Patient's PPT (m2)
Table 1
Dosage regimen for adults and adolescents with renal insufficiency weighing more than 50 kg
| Severity of renal failure | Creatinine clearance (ml/min/1.73 m2) | Dosage regimen |
| Normal kidney function | > 80 | from 500 to 1500 mg 2 times a day |
| Easy degree | 50−79 | 500 to 1000 mg 2 times a day |
| Intermediate level | 30−49 | 250 to 750 mg 2 times a day |
| Severe degree | 250 to 500 mg 2 times a day | |
| End-stage (patients on dialysis(1)) | - | 500 to 1000 mg once daily(2) |
(1) A loading dose of 750 mg is recommended on the first day of levetiracetam treatment.
(2) After dialysis, an additional dose of 250-500 mg is recommended.
For children with renal impairment, the dose of levetiracetam should be adjusted according to renal function, as the clearance of levetiracetam is related to renal function. This recommendation is based on a study in adult patients with renal impairment.
For adolescents, children, and infants, the creatinine clearance in mL/min/1.73 m2 can be calculated from the serum creatinine concentration (mg/dL) using the following formula (Schwarz 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.
Table 2
Dose adjustment recommendations for children and adolescents with renal impairment weighing less than 50 kg
| Severity of renal failure | Creatinine clearance (ml/min/1.73 m2) | Children aged 6 years and above and adolescents weighing less than 50 kg(1) |
| Normal kidney function | > 80 | 10-30 mg/kg (0.10-0.30 ml/kg) 2 times a day |
| Easy degree | 50−79 | 10-20 mg/kg (0.10-0.20 ml/kg) 2 times a day |
| Intermediate level | 30−49 | 5-15 mg/kg (0.05-0.15 ml/kg) 2 times a day |
| Severe degree | 5-10 mg/kg (0.05-0.10 ml/kg) 2 times a day | |
| End-stage (patients on dialysis) | - | 10-20 mg/kg (0.10-0.20 ml/kg) once daily (2)(3) |
(1) For dosages up to 250 mg, for doses not multiples of 250 mg, when the recommended dosage cannot be obtained by taking multiple tablets, and for patients who cannot swallow tablets, Levicitam oral solution should be used.
(2) A loading dose of 15 mg/kg (0.15 ml/kg) of levetiracetam is recommended on the first day of treatment.
(3) After dialysis, an additional dose of 5-10 mg/kg (0.05-0.10 ml/kg) is recommended.
Liver failure
No dose adjustment is required for 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, for patients with creatinine clearance <2, a 50% reduction in the daily maintenance dose is recommended.
Children
The doctor should prescribe the most appropriate dosage form, dosage and release form depending on age, body weight and calculated dose.
The tablet form is not recommended for use in children under 6 years of age and in patients who cannot swallow tablets. In this group of patients, it is preferable to use Levicitam in the form of an oral solution. In addition, the available tablet dosages are not suitable for the initial treatment of children weighing up to 25 kg, for patients who cannot swallow tablets, or for doses up to 250 mg. In all of the above cases, treatment should be started with Levicitam, oral solution.
Monotherapy
The safety and efficacy of the drug Levicitam® Asino as monotherapy in children and adolescents under 16 years of age have not been established. Data are lacking.
Adolescents (aged 16–17 years) weighing 50 kg or more with partial seizures with or without secondary generalization, who have been diagnosed with epilepsy for the first time
Adjunctive therapy for children aged 6 years and older and adolescents (12–17 years) weighing less than 50 kg
For infants and children under 6 years of age, it is advisable to use Levicitam in the form of an oral solution.
In children aged 6 years and older, Levicitam oral solution should be used for dosages up to 250 mg, for doses not multiples of 250 mg when the recommended dosage cannot be obtained by taking several tablets, and for patients who cannot swallow tablets.
For all indications, the lowest effective dose should be used. The starting dose for a child or adolescent weighing 25 kg should be 250 mg twice daily, the maximum dose is 750 mg twice daily.
Children weighing more than 50 kg are prescribed the dosage for all indications according to the scheme given for adults.
See above section “Adults (≥ 18 years) and adolescents (12–17 years) weighing 50 kg or more” for all indications.
Adjunctive therapy for infants aged 1 to 6 months
Infants are given the drug in the form of an oral solution.
Children
The tablet form of the medicine is not recommended for use in children under 6 years of age. Infants from 1 month of age and children under 6 years of age should use Levicitam oral solution.
Overdose
Symptoms
In case of overdose with levetiracetam, drowsiness, agitation, aggression, respiratory depression, depression of consciousness, coma were observed.
Treatment
In case of acute overdose, gastric lavage or induce vomiting is necessary. There is no specific antidote for levetiracetam. If necessary, symptomatic treatment should be carried out, including hemodialysis (up to 60% of levetiracetam and 74% of the main metabolite are removed).
Adverse reactions
The most commonly reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The adverse reaction profile presented is based on a pooled analysis of placebo-controlled clinical trials across all indications, involving a total of 3416 patients treated with levetiracetam. These data are supplemented by the use of levetiracetam in relevant open-label extension studies and post-marketing experience. The safety profile of levetiracetam is generally similar across age groups (adults and children) across the various established 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 below by system organ class and frequency. Adverse reactions are presented in order of decreasing seriousness and their frequency is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/100);
Infections and infestations: very common – nasopharyngitis; rare – infections.
From the blood system: infrequently - thrombocytopenia, leukopenia; rarely - neutropenia, pancytopenia, agranulocytosis.
Immune system disorders: Rare: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), hypersensitivity (including angioedema and anaphylaxis).
Nutrition and metabolism disorders: often - anorexia; infrequently - weight gain, weight loss; rarely - hyponatremia.
Psychiatric disorders: often - depression, hostility, aggression, anxiety, insomnia, irritability, nervousness; infrequently - suicide attempts and suicidal thoughts, psychotic disorders, abnormal behavior, hallucinations, anger, confusion, panic attacks, emotional lability/mood swings, agitation; rarely - suicide, personality disorders, abnormal thoughts, delirium; very rarely - obsessive-compulsive disorder**.
Nervous system disorders: very common - drowsiness, headache; common - convulsions, balance disorders, dizziness, lethargy, tremor; uncommon - amnesia, memory impairment, ataxia, coordination disorders, paresthesia, disturbance in attention; rare - hyperkinesia, choreoathetosis, dyskinesia, gait disturbance, encephalopathy, increased seizures, neuroleptic malignant syndrome*.
On the part of the organs of vision: infrequently - diplopia, blurred vision.
From the organs of hearing and balance: often - vertigo.
Cardiac: rarely - prolongation of the QT interval on the ECG.
Respiratory, thoracic and mediastinal disorders: often – cough.
Gastrointestinal: often - abdominal pain, diarrhea, dyspepsia, nausea, vomiting; rarely - pancreatitis.
Hepatobiliary system: infrequently - abnormal liver function tests; rarely - hepatitis, liver failure.
From the kidneys and urinary system: rarely - 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, muscular weakness; rare – rhabdomyolysis and increased blood creatine phosphokinase levels*.
General disorders: often - asthenia, increased fatigue.
Injury, poisoning and procedural complications: uncommon – injury.
* Prevalence is significantly higher in Japanese compared to patients of non-Japanese origin.
** Very rare cases of obsessive-compulsive disorder (OCD) have been observed in patients with a history of OCD or psychiatric disorders in post-marketing surveillance.
The risk of anorexia increases with the simultaneous use of levetiracetam with topiramate.
In cases of alopecia, hair regrowth occurred in some cases after discontinuation of levetiracetam.
Bone marrow suppression has been observed in some cases of pancytopenia.
Cases of encephalopathy were usually observed early in treatment (from a few 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 were treated with levetiracetam in placebo-controlled and open-label extension studies. Of these, 60 were treated with levetiracetam in placebo-controlled studies. Among patients aged 4 to 16 years, a total of 645 were treated with levetiracetam in placebo-controlled and open-label extension studies. Of these, 233 were treated with levetiracetam in placebo-controlled studies. In both age groups, these data are supplemented by data on the use of levetiracetam in the post-marketing period.
In addition, 101 infants under 12 months of age were treated with levetiracetam in a post-marketing safety study. No new safety data were obtained for levetiracetam in infants with epilepsy under 12 months of age.
The adverse reaction profile of levetiracetam is generally similar across age groups and across all approved epilepsy indications. The safety profile of levetiracetam in children in placebo-controlled clinical trials was consistent with the safety profile of levetiracetam in adults, except for behavioural 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%), agitation (common, 3.4%), mood swings (common, 2.1%), affective lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%) and lethargy (common, 3.9%) were observed at a higher frequency 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 incoordination (common, 3.3%) were observed at a higher frequency than in other age groups or in the overall safety profile.
A double-blind, placebo-controlled, non-inferiority pediatric safety study evaluated the effects of levetiracetam on cognitive and neuropsychological measures in children aged 4 to 16 years with partial onset seizures. In this study, levetiracetam was non-different (non-inferior) to placebo in terms of change from baseline in attention and memory on the Leiter-R scale, a population-based summary measure of memory testing, as measured by a validated, standardized instrument (Achenbach Child Behavior Checklist). Results related to behavioral and emotional functioning showed an increase in aggressive behavior in levetiracetam-treated patients, as measured in a standardized and systematic manner using validated measures (Achenbach Child Behavior Checklist). However, in patients treated with levetiracetam in a long-term open-label follow-up study, there was no average deterioration in behavioral and emotional functioning, and in particular, aggressive behavior scores were not worse than baseline.
Reporting of suspected adverse reactions
Reporting of adverse reactions after registration by a doctor
