Logufen
Ukraine
Table of Contents
- INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOGUFEN® (LOGUFEN®)
- Composition:
- Pharmacological Properties
- Clinical characteristics.
- Special precautions for use.
- Method of administration and dosage.
- Adverse reactions.
- Composition:
- Pharmacological properties.
- Clinical characteristics.
- Special precautions for use.
- Method of administration and dosage.
- Adverse reactions.
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOGUFEN® (LOGUFEN®)
Composition:
Active substance: levetiracetam;
One film-coated tablet contains levetiracetam 250 mg or 500 mg;
Excipients: maize starch, povidone, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;
Film coating:
tablets of 250 mg: Opadry (II) 85G68918 white (polyvinyl alcohol, titanium dioxide (E 171), talc, polyethylene glycol, lecithin);
tablets of 500 mg: Opadry (II) 85G52482 yellow (polyvinyl alcohol, talc, titanium dioxide (E 171), polyethylene glycol, lecithin, iron oxide yellow (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
tablets of 250 mg: oval film-coated tablets of white to almost white color, with a score line on one side;
tablets of 500 mg: oval film-coated tablets of yellow color, with a score line on one side.
Pharmacotherapeutic group. Antiepileptic drugs. Levetiracetam.
ATC code N03A X14.
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 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 the 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 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 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 antiepileptic mechanism of the drug.
Pharmacodynamic Effects
Levetiracetam provides protection against seizures in a broad range of animal models of partial and primarily generalized seizures, without causing proconvulsant effects. The main metabolite is inactive.
In humans, the drug's activity has been confirmed for both focal and generalized epileptic seizures (epileptiform discharges/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 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 milligrams (mg) per kilogram (kg) of body weight. Therefore, monitoring of plasma levels of levetiracetam is not required.
In adults and children, a significant correlation was observed between drug concentrations in saliva and plasma (the 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 close to 100%. Maximum plasma concentration (Cmax) is reached within 1.3 hours after drug intake. Steady-state is achieved within 2 days of twice-daily dosing. Cmax is typically 31 µg/mL 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 altered by food intake.
Distribution
There are no data on tissue distribution of the drug in humans. Neither levetiracetam nor its main metabolite bind significantly to plasma proteins (< 10%). The volume of distribution of levetiracetam ranges from 0.5 to 0.7 L/kg, approximately equal to total body water.
Metabolism
Metabolism of levetiracetam in humans is minimal. The primary metabolic pathway (24% of dose) is enzymatic hydrolysis of the acetamide group. Hepatic cytochrome P450 isoenzymes are not involved in the formation of the main metabolite – ucb L057. Hydrolysis of the acetamide group occurs in 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 unidentified components accounted for only 0.6% of the dose.
No interconversion of enantiomers of levetiracetam or its main metabolite was observed under in vivo conditions.
In vitro studies showed that levetiracetam and its main metabolite do not inhibit the activity of major human hepatic cytochrome P450 isoenzymes (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1, 1A2), glucuronosyltransferases (UGT1A1, UGT1A6), or epoxide hydrolase. Levetiracetam also does not inhibit glucuronidation of valproic acid in vitro.
In human hepatocyte cultures, levetiracetam had weak or no effect on conjugation of CYP1A1/2, SULT1E1, or UGT1A1. At high concentrations (680 µg/mL), levetiracetam caused weak induction of CYP2B6 and CYP3A4; however, at concentrations comparable to Cmax after repeated administration of 1500 mg twice daily, this effect was not biologically significant. In vitro and in vivo data on interactions with oral contraceptives, digoxin, and warfarin suggest that clinically significant enzyme induction is not expected in vivo. Therefore, interaction of levetiracetam with other substances is unlikely.
Elimination
The elimination half-life of the drug in plasma in adults is 7 ± 1 hour 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 by the kidneys (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 main metabolite was 66% and 24% of the dose, respectively, within the first 48 hours. Renal clearance of levetiracetam and ucb L057 is 0.6 mL/min/kg and 4.2 mL/min/kg, respectively, indicating that levetiracetam is eliminated by glomerular filtration followed by tubular reabsorption, while the main metabolite is also eliminated via active tubular secretion in addition to glomerular filtration. 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").
Renal Impairment
The apparent total clearance of levetiracetam and its main 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 elimination half-life is approximately 25 hours between dialysis sessions and 3.1 hours during dialysis. During a typical 4-hour dialysis session, 51% of levetiracetam is removed.
Hepatic Impairment
Clearance of levetiracetam 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) to children with epilepsy (aged 6 to 12 years), the elimination half-life of levetiracetam was 6 hours. Apparent clearance, corrected for body weight, was approximately 30% higher than in adult patients with epilepsy. After repeated oral administration (20–60 mg/kg/day) in children with epilepsy (aged 4–12 years), levetiracetam was rapidly absorbed. Cmax in plasma was reached within 0.5–1 hour after dosing. Cmax and area under the plasma concentration-time curve (AUC) increased linearly and were dose-dependent. The elimination half-life was approximately 5 hours, and 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 with newly diagnosed epilepsy.
As adjunctive therapy in the treatment of:
- Partial-onset seizures with or without secondary generalization in adults and children aged 6 years and older with epilepsy;
- Myoclonic seizures in adults and adolescents aged 12 years and older with juvenile myoclonic epilepsy;
- Primary generalized tonic-clonic seizures in adults and adolescents aged 12 years and older with idiopathic generalized epilepsy.
Contraindications.
Hypersensitivity to levetiracetam or to other pyrrolidone derivatives, or to any of the excipients of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
Antiepileptic drugs
Clinical data from studies in adult patients 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 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 taking enzyme-inducing antiepileptic drugs. Dose adjustment is not required.
Probenecid
Probenecid (500 mg four times daily), a drug that blocks renal tubular secretion, inhibits the renal clearance of the main metabolite of levetiracetam but not of levetiracetam itself. However, concentrations of this metabolite remain low.
Methotrexate
There have been reports that concomitant use of levetiracetam and methotrexate reduces methotrexate clearance, leading to increased/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 (luteinizing hormone and progesterone levels) were unchanged. Levetiracetam at a daily dose of 2000 mg does not alter the pharmacokinetics of digoxin and warfarin; prothrombin time values remained unchanged. Digoxin, oral contraceptives, and warfarin do not affect the pharmacokinetics of levetiracetam when 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 absorption of levetiracetam is not affected by food intake, although the rate of absorption is slightly reduced when taken with food. There are no data on interactions between levetiracetam and alcohol.
Special precautions for use.
Renal impairment
Patients with renal impairment may require dose adjustment of levetiracetam. Patients with severe hepatic dysfunction should have renal function assessed prior to determining the dose of the medicinal product (see section "Posology and method of administration").
Acute kidney injury
Very rare cases of acute kidney injury have been reported with levetiracetam use, with onset times ranging from several days to several months.
Blood count
Rare cases of blood cell count reduction (neutropenia, agranulocytosis, leukopenia, thrombocytopenia, and pancytopenia) have been reported in association with levetiracetam use, usually at the beginning of treatment. Complete blood count monitoring is recommended in patients presenting with marked weakness, fever, recurrent infections, or coagulation disorders (see section "Undesirable effects").
Suicidal behaviour
Cases of suicide, suicide attempts, suicidal ideation, and suicidal behaviour have been observed in patients treated with antiepileptic medicinal products (including levetiracetam). A meta-analysis of results from randomized placebo-controlled trials of antiepileptic drugs showed a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Due to this risk, patients should be monitored for signs of depression, suicidal ideation, and behaviour, and treatment should be adjusted as necessary. Patients (or 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 development of psychiatric signs indicating significant mood and/or personality changes. If such behaviour occurs, treatment adjustment or gradual discontinuation is recommended. For information on discontinuation, see section "Posology and method of administration".
Exacerbation of seizures
As with other antiepileptic medicinal products, levetiracetam use may rarely increase the frequency or severity of seizures. This paradoxical effect has been most frequently reported during the first month after initiation of levetiracetam or following dose increase. This effect was reversible upon discontinuation of the medicinal product or dose reduction. Patients should be advised to seek immediate medical advice if seizure control worsens. For example, lack of efficacy or worsening of seizures has been reported in patients with epilepsy associated with mutations in the alpha-8 subunit of the voltage-gated sodium channel (SCN8A).
Prolongation of the 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 known QT prolongation, in patients concurrently taking medicinal products that affect the QT interval, and in patients with relevant pre-existing 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 effects on development or sexual maturation. However, the long-term impact on learning ability, intelligence, development, endocrine functions, sexual maturation, and reproductive function in children remains unknown.
Use during pregnancy or breastfeeding
Women of childbearing potential
Specific recommendations should be provided to women of childbearing potential. Treatment with levetiracetam should be reviewed if a woman plans pregnancy. As with all antiepileptic medicinal products, 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. Whenever possible, monotherapy should be preferred, as treatment with multiple antiepileptic medicinal products may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the combination of drugs used.
Pregnancy
A large amount of post-marketing data from pregnant women who used levetiracetam (more than 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, existing epidemiological studies (approximately 100 children) do not indicate an increased risk of disorders or developmental delay of the nervous system. 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 of pregnant women receiving levetiracetam is essential.
Breastfeeding period
Levetiracetam passes into human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam is necessary 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 influence 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 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, swallowed with sufficient fluid, with or without food. When administered orally, levetiracetam may have a bitter taste.
The daily dose should be divided into 2 equal doses.
Partial seizures
The recommended dose for monotherapy (patients aged 16 years and older) and adjunctive therapy is the same and is 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 reactions. 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 may be increased up to a maximum of 1500 mg twice daily. Dose adjustments by 250 mg or 500 mg twice daily may be made every 2–4 weeks.
Children aged 6 years and older and adolescents (aged 12 to 17 years) with body weight < 50 kg
The physician should select the most appropriate dosage form, 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 the dose 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 section "Renal impairment").
Renal impairment
The daily dose should be individually adjusted according to renal function.
For dose adjustment in adults, use the table below.
To adjust the dose using the table, the creatinine clearance (CrCl) in mL/min must be determined.
CrCl in adults and adolescents with body weight > 50 kg can be calculated from serum creatinine concentration using the following formula:
[140 ─ age (years)] × body weight (kg)
CrCl (mL/min) = -------------------------------------------------------------- × 0.85 (for females).
72 × serum creatinine (mg/dL)
Then correct CrCl according to body surface area (BSA) as follows:
CrCl (mL/min)
CrCl (mL/min/1.73m²) = --------------------------- × 1.73.
Patient's BSA (m²)
Table 1
Dosage regimen in renal impairment for adults and adolescents with renal impairment and body weight > 50 kg
| Severity of renal impairment |
Creatinine clearance (mL/min/1.73 m²) |
Dosing regimen |
| Normal renal function |
> 80 |
500 - 1500 mg twice daily |
| Mild impairment |
50-79 |
500 - 1000 mg twice daily |
| Moderate impairment |
30-49 |
250 - 750 mg twice daily |
| Severe impairment |
< 30 |
250 - 500 mg twice daily |
| End-stage (patients on dialysis(1)) |
- |
500 - 1000 mg once daily(2) |
(1) On the first day of treatment with levetiracetam, a loading dose of 750 mg is recommended.
(2) After dialysis, an additional dose of 250–500 mg is recommended.
For children with renal impairment, the dose of levetiracetam should be adjusted according to renal function, as 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 (CrCl) 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
CrCl (ml/min/1.73 m²) = ------------------------------
Serum creatinine (mg/dl)
For children under 13 years of age and adolescent females, ks = 0.55; for adolescent males, ks = 0.7.
Table 2
Dosage adjustment recommendations for children (aged 6 years and older) and adolescents with renal impairment and body weight less than 50 kg
| Severity of renal impairment |
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 divisible by 250 mg when the recommended dosage cannot be achieved by taking multiple tablets, and for patients unable to swallow tablets, oral levetiracetam solution (100 mg/mL) 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, if creatinine clearance is < 60 mL/min/1.73 m², the maintenance daily dose should be reduced by 50%.
Children
The physician should select the most appropriate pharmaceutical form, dosage strength, and formulation of levetiracetam based on age, body weight, and dose.
Levetiracetam tablets are not recommended for children under 6 years of age. This patient group should preferably be treated with levetiracetam oral solution.
Additionally, the available tablet strengths are not recommended for initial treatment of children weighing less than 25 kg, for patients unable to swallow tablets, or for doses up to 250 mg. Age limitations related to the type of indication are provided in the section "Indications". In all the above cases, treatment should be initiated with levetiracetam 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, levetiracetam oral solution 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 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 weighing 25 kg should be 250 mg twice daily; the maximum dose is 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.
Levetiracetam tablets are 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 levetiracetam overdose include somnolence, agitation, aggression, respiratory depression, decreased level of consciousness, and coma.
Treatment
In cases 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. These data are supplemented by the use of levetiracetam in appropriate 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 according to established indications for epilepsy.
Adverse reactions reported in clinical studies (in adults, adolescents, children, and infants from 1 month of age) and during the post-marketing period are listed in Table 3, classified by system organ classes and frequency categories. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), and very rare (< 1/10000).
Table 3
| MedDRA System Organ Classes |
Frequency groupings |
||||
| Very common |
Common |
Uncommon |
Rare |
Very rare |
|
| Infections and infestations |
Nasopharyngitis |
Infection |
|||
| Blood and lymphatic system disorders |
Thrombocytopenia, leukopenia |
Pancytopenia, neutropenia, agranulocytosis |
|||
| Immune system disorders |
Drug reaction with eosinophilia and systemic symptoms (DRESS)(1), hypersensitivity (including angioedema and anaphylaxis) |
||||
| Metabolism and nutrition disorders |
Anorexia |
Decreased body weight, increased body weight |
Hyponatremia |
||
| Psychiatric disorders |
Depression, hostility/aggression, anxiety, insomnia, nervousness/irritability |
Suicide attempt, suicidal thoughts, psychotic disorders, abnormal behavior, hallucinations, anger, confusion, panic attacks, affective lability/mood changes, agitation |
Suicide, personality disorders, thought disorders, delirium |
Obsessive-compulsive disorder(2) |
|
| Nervous system disorders |
Somnolence, headache |
Seizures, balance disorder, dizziness, lethargy, tremor |
Amnesia, memory impairment, coordination disorder/ataxia, paresthesia, attention disorders |
Choreoathetosis, dyskinesia, hyperkinesia, gait disturbance, encephalopathy, seizure exacerbation, neuroleptic malignant syndrome(3) |
|
| Eye disorders |
Diplopia, blurred vision |
||||
| Ear and labyrinth disorders |
Vertigo |
||||
| Cardiac disorders |
QT interval prolongation on ECG |
||||
| Respiratory, thoracic and mediastinal disorders |
Cough |
||||
| Gastrointestinal disorders |
Abdominal pain, diarrhea, dyspepsia, vomiting, nausea |
Pancreatitis |
|||
| Hepatobiliary disorders |
Abnormal liver function tests |
Hepatic failure, hepatitis |
|||
| Renal and urinary disorders |
Acute kidney injury |
||||
| Skin and subcutaneous tissue disorders |
Rash |
Alopecia, eczema, pruritus |
Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme |
||
| Musculoskeletal and connective tissue disorders |
Muscle weakness, myalgia |
Rhabdomyolysis and elevated creatine phosphokinase in blood(3) |
|||
| General disorders |
Asthenia/fatigue |
||||
| Injury, poisoning and procedural complications |
Injury |
||||
- See description of individual adverse reactions.
(2) Very rare cases of development of obsessive-compulsive disorders (OCD) have been reported during post-marketing surveillance in patients with OCD or psychiatric disorders in medical history.
(3) The prevalence is significantly higher in Japanese patients compared to non-Japanese patients.
Description of individual adverse reactions
Multi-organ hypersensitivity reactions
Multi-organ hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms (DRESS)) have been rarely reported in patients receiving levetiracetam. Clinical manifestations may develop 2–8 weeks after initiation of treatment. These reactions are variable but usually present with fever, rash, facial swelling, lymphadenopathy, and hematological abnormalities. They may also involve various organ systems, most commonly the liver. Levetiracetam should be discontinued if multi-organ hypersensitivity reaction is suspected.
The risk of anorexia increases with concomitant use of levetiracetam and topiramate. In some cases of alopecia, recovery of hair growth has been observed after discontinuation of levetiracetam.
In cases of pancytopenia, bone marrow suppression has been observed in some instances.
Cases of encephalopathy were usually observed early in treatment (from several days to several months) and were reversible upon discontinuation of treatment.
Children
The adverse reaction profile of levetiracetam is generally similar across different age groups and all approved epilepsy indications. Safety data from placebo-controlled clinical trials in children are 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%) were observed more frequently than in other age groups or in the overall safety profile.
Assessment of the effect of levetiracetam on cognitive and neuropsychological parameters in children aged 4 to 16 years with partial seizures showed that levetiracetam did not differ from placebo (was not inferior) in terms of change from baseline in attention and memory as measured by the Leiter-R scale and total memory test score in the per-protocol population. Results related to behavioral and emotional functions indicated increased aggressive behavior in patients treated with levetiracetam, as systematically and consistently assessed using validated instruments (CBCL – Achenbach Child Behavior Checklist). However, in patients receiving levetiracetam during long-term open-label follow-up studies, no overall worsening of behavioral and emotional functions was observed on average, and aggressive behavior scores did not deteriorate compared to baseline.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at: https://aisf.dec.gov.ua.
Shelf life.
3 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25°C.
Keep out of reach of children.
Packaging.
10 tablets in a blister; 3 or 6 blisters in a cardboard pack.
Prescription status.
Prescription only.
Manufacturer.
Kusum Healthcare Pvt Ltd.
Manufacturer's address and site of operation.
SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.
INSTRUCTIONS
for medical use of medicinal product
LOGUFEN®
(LOGUFEN®)
Composition:
Active substance: levetiracetam;
One film-coated tablet contains 250 mg or 500 mg of levetiracetam;
Excipients: maize starch, povidone, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;
Film coating:
250 mg tablets: Opadry (II) 85G68918 white (polyvinyl alcohol, titanium dioxide (E 171), talc, polyethylene glycol, lecithin);
500 mg tablets: Opadry (II) 85G52482 yellow (polyvinyl alcohol, talc, titanium dioxide (E 171), polyethylene glycol, lecithin, yellow iron oxide (E 172)).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
250 mg tablets: oval film-coated tablets, white to almost white, with a score line on one side;
500 mg tablets: oval film-coated tablets, yellow, with a score line on one side.
Pharmacotherapeutic group. Antiepileptic drugs. Levetiracetam.
ATC code N03A X14.
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 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 assumed 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 the 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 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 corresponding analogs for synaptic vesicle protein 2A correlated with their anticonvulsant potency in models of audiogenic epilepsy in mice. These findings suggest that the interaction between levetiracetam and synaptic vesicle protein 2A may partially explain the drug's antiepileptic mechanism of action.
Pharmacodynamic effects
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/photoparoxysmal response), indicating a broad pharmacological profile of levetiracetam.
Pharmacokinetics.
Levetiracetam is characterized by high solubility and permeability. Its pharmacokinetics are linear, time-independent, and exhibit low inter- and intra-subject variability. After repeated administration, clearance does not change. No 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 milligrams (mg) per kilogram (kg) of body weight. Therefore, monitoring plasma levels of levetiracetam is unnecessary.
In adults and children, a strong correlation was observed between drug concentrations in saliva and plasma (the saliva/plasma concentration ratio ranged from 1 to 1.7 after administration of tablets for oral use and 4 hours after administration of the oral solution).
Adults and adolescents
Absorption
Levetiracetam is rapidly absorbed after oral administration. Absolute oral bioavailability is close to 100%. Maximum plasma concentration (Cmax) is reached within 1.3 hours after drug intake. Steady-state concentrations are achieved within 2 days of twice-daily dosing. Cmax typically reaches 31 µg/mL and 43 µg/mL after a single 1000 mg dose and repeated 1000 mg doses twice daily, respectively. The extent of absorption is dose-independent and not affected by food.
Distribution
There are no data on tissue distribution 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 the 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. Metabolite ucb L057 is pharmacologically inactive.
Two minor metabolites have also been identified. One results from hydroxylation of the pyrrolidone ring (1.6% of the dose), and the other from ring opening of the pyrrolidone moiety (0.9% of the dose).
Other unidentified components accounted for only 0.6% of the dose.
No interconversion of enantiomers of levetiracetam or its primary metabolite was observed under in vivo conditions.
In vitro studies showed that levetiracetam and its primary metabolite do not inhibit the activity of major human hepatic cytochrome P450 isoenzymes (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1, 1A2), glucuronosyltransferases (UGT1A1, UGT1A6), or epoxide hydrolase. Levetiracetam also does not inhibit glucuronidation of valproic acid in vitro.
In human hepatocyte cultures, levetiracetam had weak or no effect on conjugation of CYP1A1/2, SULT1E1, or UGT1A1. At high concentrations (680 µg/mL), levetiracetam caused weak induction of CYP2B6 and CYP3A4; however, at concentrations comparable to Cmax after repeated 1500 mg twice-daily dosing, this effect was not biologically significant. In vitro and in vivo data on interactions with oral contraceptives, digoxin, and warfarin indicate that clinically significant enzyme induction is unlikely in vivo. Therefore, interactions between levetiracetam and other substances are improbable.
Elimination
The elimination half-life of the drug in plasma in adults is 7 ± 1 hour 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, approximately 95% of the 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 was 66% and 24% of the dose, respectively, within the first 48 hours. Renal clearance of levetiracetam and ucb L057 is 0.6 mL/min/kg and 4.2 mL/min/kg, respectively, indicating that levetiracetam is eliminated via glomerular filtration followed by tubular reabsorption, while the primary metabolite is also excreted via active tubular secretion in addition to glomerular filtration. Levetiracetam elimination correlates with creatinine clearance.
Elderly patients
In elderly patients, elimination half-life increases by approximately 40% (10–11 hours). This is related to 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 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 is approximately 25 hours between dialysis sessions and 3.1 hours during dialysis. During a typical 4-hour dialysis session, 51% of levetiracetam is removed.
Hepatic impairment
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) to children with epilepsy (aged 6 to 12 years), the elimination half-life of levetiracetam was 6 hours. Apparent clearance, corrected for body weight, was approximately 30% higher than in adult patients with epilepsy. After repeated oral administration (20–60 mg/kg/day) in children with epilepsy (aged 4–12 years), levetiracetam was rapidly absorbed. Cmax in plasma was reached within 0.5–1 hour after dosing. Cmax and area under the plasma concentration-time curve (AUC) increased linearly and were dose-dependent. The elimination half-life was approximately 5 hours, and 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 adolescents aged 16 years and older with newly diagnosed epilepsy.
As adjunctive therapy in the treatment of:
- Partial seizures with or without secondary generalization in adults and children aged 6 years and older with epilepsy;
- Myoclonic seizures in adults and adolescents aged 12 years and older with juvenile myoclonic epilepsy;
- Primary generalized tonic-clonic seizures in adults and adolescents aged 12 years and older with idiopathic generalized epilepsy.
Contraindications.
Hypersensitivity to levetiracetam or to other pyrrolidone derivatives, as well as to any of the excipients of the medicinal product.
Interaction with other medicinal products and other forms of interactions.
Antiepileptic drugs
Clinical data from adult patients indicate that levetiracetam does not affect serum concentrations of established 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 interactions of the medicinal product in pediatric patients, as well as in adults receiving up to 60 mg/kg/day of levetiracetam.
A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (aged 4 to 17 years) confirmed that adjunctive therapy with oral levetiracetam did not affect the steady-state serum concentrations of concurrently administered carbamazepine and valproate. However, data indicate that the clearance of levetiracetam is 20% higher in children taking enzyme-inducing anticonvulsants. Dose adjustment is not required.
Probenecid
Probenecid (500 mg four times daily), a drug that blocks tubular secretion, inhibits the renal clearance of the major 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 methotrexate clearance, leading to increased/prolonged methotrexate blood concentrations to potentially toxic levels. Serum levels of methotrexate and levetiracetam should be closely monitored in patients receiving treatment with both drugs simultaneously.
Oral contraceptives and pharmacokinetic interactions with other drugs
Levetiracetam at a daily dose of 1000 mg does not alter the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone levels) were unchanged. Levetiracetam at a daily dose of 2000 mg does not alter the pharmacokinetics of digoxin and warfarin; prothrombin time values remained unchanged. Digoxin, oral contraceptives, and warfarin do not affect the pharmacokinetics of levetiracetam when administered concomitantly.
Laxatives
In isolated cases, reduced effectiveness of levetiracetam has been reported when osmotic laxative macrogol was administered concomitantly with oral levetiracetam. Therefore, macrogol should not be taken orally within one hour before or one hour after administration of levetiracetam.
Food and alcohol
The extent of absorption of levetiracetam is not affected by food intake, although the rate of absorption is slightly reduced when taken with food. There are no data on interaction between levetiracetam and alcohol.
Special precautions for use.
Renal impairment
Patients with renal impairment may require adjustment of the levetiracetam dosage. Patients with severe hepatic dysfunction are recommended to have renal function assessed before determining the dosage regimen (see section "Dosage and administration").
Acute kidney injury
Very rare cases of acute kidney injury have been reported with levetiracetam use, with onset ranging from several days to several months.
Blood count
Rare cases of blood cell count reduction (neutropenia, agranulocytosis, leukopenia, thrombocytopenia, and pancytopenia) have been reported in association with levetiracetam use, usually at the beginning of treatment. Complete blood count monitoring is recommended in patients presenting with significant weakness, fever, recurrent infections, or bleeding disorders (see section "Adverse reactions").
Suicidal behavior
Cases of suicide, suicide attempts, suicidal thoughts, and suicidal behavior have been observed in patients treated with 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 behavior. The mechanism of this risk is not understood. Due to this risk, patients should be monitored for signs of depression, suicidal thoughts, and behavior, and treatment should be adjusted as necessary. Patients (or their caregivers) should be advised to report any symptoms of depression, suicidal thoughts, or behavior to their physician.
Unusual or aggressive behavior
Levetiracetam may cause psychiatric symptoms and behavioral disturbances, including irritability and aggression. Patients taking levetiracetam should be monitored for the development of psychiatric signs indicating significant changes in mood and/or personality. If such behavior occurs, treatment adjustment or gradual discontinuation is recommended. For information on discontinuation, see the "Dosage and administration" section.
Exacerbation of seizures
As with other antiepileptic drugs, levetiracetam use may rarely increase the frequency or severity of seizures. This paradoxical effect has most frequently been reported within 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 consultation if seizure exacerbation occurs. For example, lack of efficacy or worsening of seizures has been reported in patients with epilepsy associated with mutations in the alpha subunit 8 of the voltage-gated sodium channel (SCN8A).
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 known QT interval prolongation, in patients concurrently taking medicinal products affecting the QT interval, and in patients with relevant 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.
Use during pregnancy or breastfeeding.
Women of childbearing potential
Specific recommendations should be provided to women of childbearing potential. Levetiracetam treatment should be reviewed if a woman plans 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. Whenever possible, monotherapy should be preferred, as treatment with multiple antiepileptic drugs may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the combination of drugs used.
Pregnancy
Large amounts of post-marketing data from pregnant women using levetiracetam (over 1800 women, of whom 1500 used the drug during the first trimester) do not indicate an increased risk of major congenital malformations. There is only limited information 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 disorders or delays in nervous system development. Levetiracetam may be used during pregnancy if, after careful assessment, it is considered clinically necessary. In such cases, the lowest effective dose is recommended.
Physiological changes during pregnancy may alter levetiracetam concentrations. Decreased plasma concentrations of levetiracetam have been observed during pregnancy. This reduction is most pronounced in the third trimester (up to 60% of pre-pregnancy baseline concentration). Appropriate clinical monitoring should be ensured for pregnant women receiving levetiracetam.
Breastfeeding period
Levetiracetam passes into human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam use is necessary during breastfeeding, the benefits and risks of treatment should be weighed against the importance of breastfeeding.
Effect on reproductive function
No effects on reproductive function were observed in animal studies. The potential risk in humans is unknown due to the lack of available clinical data.
Ability to influence 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 high concentration, such as driving a car or operating machinery. Patients are advised to refrain from driving vehicles and operating machinery until it is established that their ability to perform such activities is not impaired.
Method of administration and dosage.
Tablets should be taken orally, swallowed with sufficient fluid, 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 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 administered on the first day of treatment. However, a lower initial dose of 250 mg twice daily may be used at the physician’s discretion based on a risk-benefit assessment of seizure frequency reduction versus potential adverse reactions. This dose may be increased to 500 mg twice daily after 2 weeks.
Depending on the clinical picture and tolerability, the daily dose may be increased up to a maximum of 1500 mg twice daily. Dose adjustments by 250 mg or 500 mg twice daily may be made every 2–4 weeks.
Children aged 6 years and older and adolescents (aged 12 to 17 years) with body weight < 50 kg
The physician should select the most appropriate pharmaceutical form, dosage strength, and presentation 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 treatment 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 section “Renal impairment”).
Renal impairment
The daily dose should be individually adjusted according to renal function.
For dose adjustment in adults, use the table below.
To adjust the dose using the table, the creatinine clearance (CrCl) in mL/min must be determined.
CrCl in adults and adolescents with body weight > 50 kg can be calculated from serum creatinine concentration using the Cockcroft-Gault formula:
[140 ─ age (years)] × body weight (kg)
CrCl (mL/min) = -------------------------------------------------------------- × 0.85 (for women)
72 × serum creatinine (mg/dL)
Then, CrCl should be corrected for body surface area (BSA) as follows:
CrCl (mL/min)
CrCl (mL/min/1.73 m²) = --------------------------- × 1.73
BSA of patient (m²)
Table 1
Dosage regimen in renal impairment for adults and adolescents with renal impairment and body weight > 50 kg
| Severity of renal impairment |
Creatinine clearance (mL/min/1.73 m²) |
Dosing regimen |
| Normal renal function |
> 80 |
500 - 1500 mg twice daily |
| Mild impairment |
50-79 |
500 - 1000 mg twice daily |
| Moderate impairment |
30-49 |
250 - 750 mg twice daily |
| Severe impairment |
< 30 |
250 - 500 mg twice daily |
| End-stage (patients on dialysis(1)) |
- |
500 - 1000 mg once daily(2) |
(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 kidney function, as levetiracetam clearance is related to renal function. This recommendation is based on a study conducted in adult patients with impaired kidney 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 |
50–79 |
10–20 mg/kg (0.10–0.20 mL/kg) twice daily |
| Moderate |
30–49 |
5–15 mg/kg (0.05–0.15 mL/kg) twice daily |
| Severe |
< 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 divisible by 250 mg when the recommended dosage cannot be achieved by taking several tablets, and for patients who cannot swallow tablets, oral solution of levetiracetam (100 mg/mL) 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, if creatinine clearance is < 60 mL/min/1.73 m², the maintenance daily dose should be reduced by 50%.
Children
The physician should select the most appropriate pharmaceutical form, dosage strength, and formulation of levetiracetam based on age, body weight, and dose.
Levetiracetam in tablet form 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 recommended for initial treatment of children weighing less than 25 kg, for patients who cannot swallow tablets, or for doses up to 250 mg. Age limitations related to the type of indication are provided in the section "Indications". In all the above cases, treatment should be initiated with levetiracetam 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) with body weight ≥ 50 kg with partial-onset seizures with or without secondary generalization, newly diagnosed with epilepsy
See section above «Adults (≥ 18 years) and adolescents (12–17 years) with body weight ≥ 50 kg».
Adjunctive therapy in children aged 6 years and older and adolescents (12–17 years) with body weight < 50 kg
Oral solution of levetiracetam is preferred for infants and children under 6 years of age.
For children aged 6 years and older, levetiracetam oral solution 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 who cannot 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.
For children with body weight over 50 kg, dosing for all indications should follow the regimen described for adults.
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.
Levetiracetam in tablet form 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 cases of levetiracetam overdose include somnolence, agitation, aggression, respiratory depression, depressed level of 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, increased fatigue, and dizziness. The adverse reaction profile presented is based on a pooled analysis of data from placebo-controlled clinical trials. These data are supplemented by the use of levetiracetam in appropriate long-term open-label studies, as well as post-marketing experience. The safety profile of levetiracetam is generally similar across different age groups (adults and children) when used for various approved indications in epilepsy.
Adverse reactions reported in clinical studies (in adults, adolescents, children, and infants from 1 month of age) and during the post-marketing period are listed in Table 3 by system organ classes, with frequencies categorized as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), and very rare (< 1/10000).
Table 3
| MedDRA System Organ Classes |
Frequency groups |
||||
| Very common |
Common |
Uncommon |
Rare |
Very rare |
|
| Infections and infestations |
Nasopharyngitis |
Infection |
|||
| Blood and lymphatic system disorders |
Thrombocytopenia, leukopenia |
Pancytopenia, neutropenia, agranulocytosis |
|||
| Immune system disorders |
Drug reaction with eosinophilia and systemic symptoms (DRESS), Hypersensitivity (including angioedema and anaphylaxis) |
||||
| Metabolism and nutrition disorders |
Anorexia |
Weight decreased, weight increased |
Hypoaesthesia |
||
| Psychiatric disorders |
Depression, hostility/aggression, anxiety, insomnia, nervousness/irritability |
Suicide attempt, suicidal ideation, psychotic disorders, abnormal behaviour, hallucinations, anger, confusion, panic attacks, affective lability/mood changes, agitation |
Suicide, personality disorders, thought disorders, delirium |
Obsessive-compulsive disorders |
|
| Nervous system disorders |
Somnolence, headache |
Seizures, coordination disorder, dizziness, lethargy, tremor |
Amnesia, memory impairment, coordination disorder/ataxia, paresthesia, attention disorders |
Choreoathetosis, dyskinesia, hyperkinesia, gait disturbance, encephalopathy, seizure exacerbation, neuroleptic malignant syndrome* |
|
| Eye disorders |
Diplopia, blurred vision |
||||
| Ear and labyrinth disorders |
Vertigo |
||||
| Cardiac disorders |
QT interval prolongation on ECG |
||||
| Respiratory, thoracic and mediastinal disorders |
Cough |
||||
| Gastrointestinal disorders |
Abdominal pain, diarrhea, dyspepsia, vomiting, nausea |
Pancreatitis |
|||
| Hepatobiliary disorders |
Liver function test abnormal |
Liver failure, hepatitis |
|||
| Renal and urinary disorders |
Acute kidney injury |
||||
| Skin and subcutaneous tissue disorders |
Rash |
Alopecia, eczema, pruritus |
Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme |
||
| Musculoskeletal and connective tissue disorders |
Muscle weakness, myalgia |
Rhabdomyolysis and elevated creatine phosphokinase in blood* |
|||
| General disorders |
Asthenia/fatigue |
||||
| Injury, poisoning and procedural complications |
Injury |
||||
- See description of individual adverse reactions.
(2) Very rare cases of development of obsessive-compulsive disorder (OCD) have been reported during post-marketing surveillance in patients with OCD or psychiatric disorders in medical history.
(3) The prevalence is significantly higher in Japanese patients compared to non-Japanese patients.
Description of individual adverse reactions
Multi-organ hypersensitivity reactions
Multi-organ hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms (DRESS)) have been rarely reported in patients receiving levetiracetam. Clinical manifestations may develop 2–8 weeks after initiation of treatment. These reactions are variable but usually present with fever, rash, facial swelling, lymphadenopathy, and hematological abnormalities. They may also involve various organ systems, most commonly the liver. Levetiracetam should be discontinued if multi-organ hypersensitivity reaction is suspected.
The risk of anorexia increases when levetiracetam is used concomitantly with topiramate. In some cases of alopecia, hair regrowth was observed after discontinuation of levetiracetam.
In cases of pancytopenia, bone marrow suppression was observed in some instances.
Cases of encephalopathy were usually observed at the beginning of treatment (within days to months) and were reversible upon discontinuation of treatment.
Children
The adverse reaction profile of levetiracetam is generally similar across different age groups and all approved epilepsy indications. Safety data from placebo-controlled clinical trials in children were consistent with the safety profile of levetiracetam in adults, except for behavioral and psychiatric adverse reactions, which were more frequent in children than in adults. In children 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.
Assessment of the effect of levetiracetam on cognitive and neuropsychological parameters in children aged 4 to 16 years with partial seizures showed that levetiracetam was not inferior to placebo regarding change from baseline in attention and memory as measured by the Leiter-R scale and total memory score in the per-protocol population. Results related to behavioral and emotional functions indicated increased aggressive behavior in patients treated with levetiracetam, as systematically and consistently assessed using validated instruments (CBCL – Achenbach Child Behavior Checklist). However, in patients receiving levetiracetam during long-term open-label follow-up studies, no overall worsening of behavioral and emotional functions was observed on average, and aggressive behavior scores did not deteriorate compared to baseline.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life.
3 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25°C.
Keep out of reach of children.
Packaging.
10 tablets in a blister; 3 or 6 blisters in a cardboard box.
Prescription category.
Prescription only.
Manufacturer.
LLC "GLEDPHARM LTD".
Manufacturer's location and address of business activity.
54 Davydovskoho Hryhorii Street, Sumy, Sumy region, 40020, Ukraine.