Logufen
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOGUFEN® (LOGUFEN®)
Composition:
Active substance: levetiracetam;
1 ml of solution contains levetiracetam 100 mg;
Excipients: maltitol liquid (E 965), methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), glycerol, potassium acesulfame (E 950), anhydrous citric acid, sodium citrate, sodium dihydrogen phosphate dihydrate, sodium hydroxide, lemon flavoring, purified water.
Pharmaceutical form. Oral solution.
Main physicochemical characteristics: clear solution with a characteristic odor.
Pharmacotherapeutic group. Antiepileptic drugs. Levetiracetam.
ATC code N03A X14.
Pharmacological properties.
Pharmacodynamics.
Levetiracetam is a pyrrolidone derivative (S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine-acetamide) and differs chemically from known antiepileptic drugs.
Mechanism of action
The mechanism of action of levetiracetam is not fully understood, but it has been established that it differs from the mechanisms of action of known antiepileptic agents. 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 the potency of their anticonvulsant effects in audiogenic seizure models in mice. These findings suggest that the interaction between levetiracetam and synaptic vesicle protein 2A may partially explain the antiepileptic mechanism of action of the drug.
Pharmacodynamic effects
Levetiracetam provides protection against seizures in a broad range of animal models of partial and primarily generalized seizures, without exhibiting proconvulsant effects. The main metabolite is inactive.
In humans, the drug's activity has been confirmed for both focal and generalized epileptic seizures (epileptiform manifestations/photo-epileptic 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 levels of the drug can be predicted based on the oral dose of levetiracetam expressed in milligrams per kilogram of body weight. Therefore, monitoring plasma levels of levetiracetam is not necessary.
In adults and children, a significant correlation was observed between drug concentration 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 oral solution).
Adults and adolescents
Absorption
Levetiracetam is rapidly absorbed after oral administration. Absolute oral bioavailability is nearly 100%. Maximum plasma concentration (Cmax) is reached within 1.3 hours after drug intake. Steady state is achieved within 2 days of twice-daily administration. 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 independent of dose and is not altered by food.
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 main metabolic pathway (24% of dose) is enzymatic hydrolysis of the acetamide group. Hepatic cytochrome P450 isoenzymes are not involved in the formation of the main metabolite – ucb L057. Hydrolysis of the acetamide group was observed in a wide range of tissues, including blood cells. The metabolite ucb L057 is pharmacologically inactive.
Two minor metabolites have also been identified. One is formed by hydroxylation of the pyrrolidone ring (1.6% of dose), the other by cleavage 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 did not inhibit the activity of major human hepatic cytochrome P450 isoenzymes (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1, and 1A2), glucuronosyltransferases (UGT1A1 and UGT1A6), or epoxide hydrolase. Levetiracetam also did not inhibit glucuronidation of valproic acid in vitro.
In human hepatocyte cultures, levetiracetam showed weak or no effect on conjugation of CYP1A1/2, SULT1E1, or UGT1A1.
Levetiracetam caused weak induction of CYP2B6 and CYP3A4.
In vitro and in vivo data on interactions with oral contraceptives, digoxin, and warfarin suggest that clinically significant enzyme induction is not expected in vivo. Therefore, drug interactions between levetiracetam and other medicinal products, or vice versa, are 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 administration. Mean total clearance is 0.96 mL/min/kg.
Approximately 95% of the administered dose is excreted via 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 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 and 4.2 mL/min/kg, respectively, indicating glomerular filtration of levetiracetam followed by tubular reabsorption, while the main metabolite is also excreted via active tubular secretion in addition to glomerular filtration. Levetiracetam excretion correlates with creatinine clearance.
Elderly patients
In elderly patients, the elimination half-life increases by approximately 40% (10–11 hours), which 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 levetiracetam is recommended for patients with moderate to severe renal impairment according to creatinine clearance (see section "Dosage and administration").
In patients with end-stage renal disease and anuria, the elimination half-life is approximately 25 hours (between dialysis sessions) and 3.1 hours (during dialysis). Approximately 51% of levetiracetam is removed during a typical 4-hour dialysis session.
Hepatic impairment
No relevant changes in levetiracetam clearance were observed 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 "Dosage and administration").
Pediatric population
Children aged 4 to 12 years
After a single dose (20 mg/kg) administered 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 to 12 years), levetiracetam was rapidly absorbed. Cmax 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.
Infants and children aged 1 month to 4 years
After a single dose (20 mg/kg) of oral solution (100 mg/mL) administered to children with epilepsy (aged 1 month to 4 years), levetiracetam was rapidly absorbed, with Cmax observed approximately 1 hour after dosing. Pharmacokinetic parameters indicate a shorter elimination half-life (5.3 hours) compared to adults (7.2 hours), and faster apparent clearance (1.5 mL/min/kg) compared to adults (0.96 mL/min/kg).
Results from another population pharmacokinetic analysis conducted in patients aged 1 month to 16 years indicate a significant correlation between body weight and apparent clearance (clearance increases with increasing body weight) and apparent volume of distribution. Age also influenced both parameters. This effect was more pronounced in younger infants, decreased with increasing age, and was negligible in children approximately 4 years of age.
Data from both population pharmacokinetic analyses indicate an approximately 20% increase in apparent clearance of levetiracetam when co-administered with enzyme-inducing antiepileptic drugs.
Clinical characteristics.
Indications.
Monotherapy (first-line treatment) for the treatment of:
- Partial-onset seizures with or without secondary generalization in adults and adolescents aged 16 years and older who have newly diagnosed epilepsy.
As adjunctive therapy in the treatment of:
- Partial-onset seizures with or without secondary generalization in adults and children aged 1 month 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 interactions.
Antiepileptic drugs
Levetiracetam does not affect other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone), and these drugs, in turn, do not affect the pharmacokinetics of levetiracetam.
As in adults, there are no data on clinically significant interactions of the medicinal product in pediatric patients receiving up to 60 mg/kg/day of levetiracetam.
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 receiving enzyme-inducing antiepileptic drugs. Dose adjustment is not required.
Probenecid
Probenecid (500 mg four times daily)—a drug that blocks tubular secretion—reduces the renal clearance of the main metabolite, but not of levetiracetam itself. However, concentrations of this metabolite remain low.
Methotrexate
Concomitant use of levetiracetam and methotrexate has been reported to reduce methotrexate clearance, leading to increased/prolonged methotrexate blood concentrations to potentially toxic levels. Methotrexate and levetiracetam blood levels should be closely monitored in patients receiving both drugs concomitantly.
Oral contraceptives and pharmacokinetic interactions with other drugs
Levetiracetam at a daily dose of 1000 mg does not alter the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); endocrine parameters (levels of luteinizing hormone and progesterone) were unchanged. Levetiracetam at a daily dose of 2000 mg does not alter the pharmacokinetics of digoxin and warfarin; prothrombin time remained unchanged. Digoxin, oral contraceptives, and warfarin, in turn, do not affect the pharmacokinetics of levetiracetam when co-administered.
Laxatives
In isolated cases, reduced effectiveness of levetiracetam has been reported when administered concomitantly with the osmotic laxative macrogol and 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, although the rate of absorption is somewhat 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 dosage adjustment of levetiracetam. Patients with severe hepatic dysfunction should have renal function assessed prior to determining dosage (see section "Dosage and administration").
Acute kidney injury
Acute kidney injury has been reported very rarely with levetiracetam use, with onset ranging from several days to several months.
Blood cell counts
Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leukopenia, thrombocytopenia, and pancytopenia) have been reported with levetiracetam use, usually at the beginning of treatment. Complete blood count monitoring is recommended in patients who develop significant weakness, fever, recurrent infections, or bleeding disorders (see section "Side effects").
Suicidal behavior
Suicide, suicide attempts, suicidal ideation, and suicidal behavior have been observed in patients treated with antiepileptic drugs, including levetiracetam. A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is not known. Due to this risk, patients should be monitored for signs of depression, suicidal thoughts, and behavior, and treatment adjusted as necessary. Patients (or their caregivers) should be advised to report any symptoms of depression, suicidal ideation, or behavior to their physician.
Abnormal and aggressive behavior
Levetiracetam may cause psychiatric symptoms and behavioral disturbances, including irritability and aggression. Patients receiving levetiracetam should be monitored for the development of psychiatric disorders, particularly significant mood and/or personality changes. If such behavior occurs, therapy should be adjusted or gradual discontinuation of levetiracetam considered. If discontinuation is necessary, it should be done according to the recommendations described in the section "Dosage and administration".
Exacerbation of seizures
As with other antiepileptic drugs, levetiracetam may rarely increase the frequency and severity of seizures. This paradoxical effect has mostly been reported within the first month after initiation or dose increase of levetiracetam and is usually reversible upon discontinuation or dose reduction. Patients should be advised to contact their physician immediately if there is worsening of epilepsy. 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).
QT interval prolongation on electrocardiogram
Rare cases of QT interval prolongation on electrocardiogram have been reported in the post-marketing period. Levetiracetam should be used with caution in patients with QT prolongation syndrome; when co-administered with medicinal products affecting the QT interval; and in patients with underlying cardiac conditions or electrolyte imbalances.
Children
Available data in pediatric patients do not indicate effects on growth and sexual maturation. However, long-term effects on learning abilities, intelligence, growth, endocrine functions, sexual maturation, and reproductive potential in children have not been studied.
Excipients
The medicinal product contains methylparaben (E 218) and propylparaben (E 216), which may cause allergic reactions (possibly delayed). The product also contains liquid maltitol; therefore, consultation with a physician is recommended before taking this medicinal product if intolerance to certain sugars has been diagnosed.
This medicinal product contains less than 1 mmol sodium per dose, i.e., essentially "sodium-free".
Use during pregnancy or breastfeeding.
Women of childbearing potential
Special advice should be given to women of childbearing potential. Treatment with levetiracetam should be reviewed if a woman plans pregnancy. As with all antiepileptic drugs, abrupt withdrawal 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 is 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
A large amount of post-marketing data from pregnant women treated with levetiracetam (over 1800 women, including 1500 treated during the first trimester) does not indicate an increased risk of major congenital malformations. There is only limited data available on the neurodevelopment of children exposed to levetiracetam monotherapy in utero. However, existing epidemiological studies (approximately 100 children) do not indicate an increased risk of neurodevelopmental disorders or delay. 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 affect levetiracetam concentrations. Decreased plasma concentrations of levetiracetam have been observed during pregnancy, with a more pronounced reduction in the third trimester (up to 60% of pre-pregnancy baseline concentrations). Pregnant women receiving levetiracetam therapy should receive appropriate clinical monitoring.
Breastfeeding period
Levetiracetam passes into human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam must be used during breastfeeding, the benefits and risks of treatment should be weighed against the importance of breastfeeding.
Effect on reproductive function
No effect on reproductive function was observed in animal studies. The potential risk in humans is unknown due to 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 high concentration, such as driving a car or operating machinery. Patients are advised to refrain from driving vehicles or operating machinery until it is established that their ability to perform such activities is not impaired.
Dosage and Administration
The medication should be taken orally, independent of food intake. The oral solution may be taken after dilution in a glass of water or a feeding bottle. A bitter taste of levetiracetam may be experienced after oral administration.
Partial Seizures
The recommended dose for monotherapy (patients aged 16 years and older) and adjunctive therapy is the same and is specified below.
All Indications
Adults (≥18 years) and adolescents (12–17 years) with body weight ≥50 kg
The initial therapeutic dose is 500 mg twice daily. This dose may be initiated on the first day of treatment. However, a lower initial dose of 250 mg twice daily may be prescribed by the physician based on an assessment of seizure frequency reduction versus potential adverse effects. This dose may be increased to 500 mg twice daily after 2 weeks.
Depending on clinical response and tolerability, the daily dose may be increased up to 1500 mg twice daily. The dose may be increased or decreased by 500 mg twice daily every 2–4 weeks.
Adolescents (12–17 years) with body weight <50 kg and children from 1 month of age
The physician should select the most appropriate pharmaceutical form, dosage, and presentation based on body weight, age, and required dose. Dosage adjustment according to body weight is described in the section "Children".
Discontinuation of Treatment
If discontinuation of treatment is necessary, levetiracetam should be withdrawn 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 infants aged 6 months, children, and adolescents with body weight <50 kg, reduce the dose by no more than 10 mg/kg twice daily every two weeks; for infants under 6 months of age, reduce the dose by no more than 7 mg/kg twice daily every two weeks).
Special Patient Groups
Elderly patients (≥65 years)
Dosage adjustment in elderly patients is required only in case of renal impairment (see section "Patients with Renal Impairment" below).
Patients with Renal Impairment
The daily dose of levetiracetam should be individually adjusted.
For adult patients, the dose should be adjusted as shown in Table 1 below. To adjust the dose, the patient's creatinine clearance (CrCl) in mL/min must be determined.
In adults and adolescents with body weight ≥50 kg, CrCl in mL/min can be calculated from serum creatinine level (mg/dL) using the following formula:
[140 ─ age (years)] × body weight (kg)
CrCl (mL/min) = -------------------------------------------------------------- × 0.85 (for females)
72 × serum creatinine (mg/dL)
Then, CrCl should be corrected 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 Adjustment Recommendations for Adult Patients and Adolescents with Body Weight ≥50 kg and Renal Impairment
| Severity of renal impairment |
Creatinine clearance (mL/min/1.73 m²) |
Dosing regimen |
| Normal renal function |
≥ 80 |
500 to 1500 mg twice daily |
| Mild |
50–79 |
500 to 1000 mg twice daily |
| Moderate |
30–49 |
250 to 750 mg twice daily |
| Severe |
<30 |
250 to 500 mg twice daily |
| End-stage (patients on dialysis (1)) |
|
500 to 1000 mg once daily (2) |
(1) On the first day of treatment, a loading dose of levetiracetam 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 correlated with renal function. This recommendation is based on a study conducted in adult patients with impaired renal function.
For adolescents, children, and infants, GFR in mL/min/1.73 m² can be calculated from serum creatinine (mg/dL) using the following formula (Schwartz formula):
height (cm) × ks
GFR (mL/min/1.73 m²) = ------------------------------
serum creatinine (mg/dL)
In full-term infants under 1 year of age, ks = 0.45; in children under 13 years and adolescent females, ks = 0.55; in adolescent males, ks = 0.7.
Table 2
Dose adjustment recommendations for infants, children, and adolescents weighing less than 50 kg with impaired renal function
| Severity of renal impairment |
Creatinine clearance (ml/min/1.73 m²) |
Dosage and frequency of administration(1) |
|
| Infants aged 1 to < 6 months |
Infants aged 6 to 23 months, children and adolescents with body weight less than 50 kg |
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| Normal renal function |
≥ 80 |
7–21 mg/kg (0.07–0.21 ml/kg) twice daily |
10–30 mg/kg (0.1–0.3 ml/kg) twice daily |
| Mild |
50–79 |
7–14 mg/kg (0.07–0.14 ml/kg) twice daily |
10–20 mg/kg (0.1–0.2 ml/kg) twice daily |
| Moderate |
30–49 |
3.5–10.5 mg/kg (0.035–0.105 ml/kg) twice daily |
5–15 mg/kg (0.05–0.15 ml/kg) twice daily |
| Severe |
<30 |
3.5–7 mg/kg (0.035–0.07 ml/kg) twice daily |
5–10 mg/kg (0.05–0.1 ml/kg) twice daily |
| End-stage (patients undergoing dialysis) |
|
7–14 mg/kg (0.07–0.14 ml/kg) once daily (2) (4) |
10–20 mg/kg (0.1–0.2 ml/kg) once daily (3) (5) |
(1) For doses up to 250 mg, for doses not divisible by 250 mg when the recommended dosage cannot be achieved by administering several tablets, and for patients unable to swallow tablets, Logufen® 100 mg/ml oral solution should be used.
(2) On the first day of treatment, a loading dose of levetiracetam 10.5 mg/kg (0.105 ml/kg) is recommended.
(3) On the first day of treatment, a loading dose of levetiracetam 15 mg/kg (0.15 ml/kg) is recommended.
(4) After dialysis, an additional dose of 3.5–7 mg/kg (0.035–0.07 ml/kg) is recommended.
(5) After dialysis, an additional dose of 5–10 mg/kg (0.05–0.1 ml/kg) is recommended.
Patients with hepatic impairment
Dose adjustment is not required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, creatinine clearance may not fully reflect the degree of renal impairment. Therefore, in patients with creatinine clearance <60 ml/min/1.73 m², the recommended daily maintenance dose should be reduced by 50%.
Children
The physician should select the most appropriate pharmaceutical form, strength, and dosage form based on age, body weight, and required dose.
Logufen®, 100 mg/ml oral solution, is preferred for infants and children under 6 years of age. Additionally, available tablet strengths are not suitable for initial treatment of children weighing less than 25 kg, for patients unable to swallow tablets, or for doses below 250 mg. In these cases, Logufen®, 100 mg/ml oral solution, should be used.
Monotherapy
The safety and efficacy of Logufen® as monotherapy in children and adolescents under 16 years of age have not been established.
Data are lacking.
Adolescents (16–17 years of age) with body weight ≥50 kg with partial-onset seizures with or without secondary generalization, newly diagnosed epilepsy
See section above titled "Adults (≥18 years) and adolescents (12–17 years) with body weight ≥50 kg".
Adjunctive therapy in infants aged 6–23 months, children (2–11 years), and adolescents (12–17 years) with body weight <50 kg
The initial therapeutic dose is 10 mg/kg twice daily.
Depending on clinical response and tolerability, the dose may be increased up to 30 mg/kg twice daily. Dose adjustments should not exceed increments or decrements of more than 10 mg/kg twice daily every two weeks. The lowest effective dose should be used for all indications.
Children with body weight of 50 kg or more should receive the same doses as adults for all indications.
For information on use in all indications, see section above titled "Adults (≥18 years) and adolescents (12–17 years) with body weight ≥50 kg".
Table 3
Recommended doses for infants from 6 months of age, children, and adolescents
| Body weight |
Initial dose – 10 mg/kg twice daily |
Maximum dose – 30 mg/kg twice daily |
| 6 kg (1) |
60 mg (0.6 ml) twice daily |
180 mg (1.8 ml) twice daily |
| 10 kg (1) |
100 mg (1 ml) twice daily |
300 mg (3 ml) twice daily |
| 15 kg (1) |
150 mg (1.5 ml) twice daily |
450 mg (4.5 ml) twice daily |
| 20 kg (1) |
200 mg (2 ml) twice daily |
600 mg (6 ml) twice daily |
| 25 kg |
250 mg twice daily |
750 mg twice daily |
| From 50 kg (2) |
500 mg twice daily |
1500 mg twice daily |
(1) For children with a body weight of 25 kg or less, treatment should be initiated with Logufen® 100 mg/mL oral solution.
(2) For children with a body weight of 50 kg or more, the same doses as for adults should be used.
Additional therapy for infants aged 1 to <6 months
The initial therapeutic dose is 7 mg/kg twice daily.
Depending on clinical response and tolerability, the dose may be increased up to 21 mg/kg twice daily. The dose should not be increased or decreased by more than 7 mg/kg twice daily every two weeks. The lowest effective dose should be used.
For infants, treatment should be initiated with Logufen® 100 mg/mL oral solution.
Table 4
Recommended doses for infants aged 1 to 6 months
| Body weight |
Initial dose – 7 mg/kg twice daily |
Maximum dose – 21 mg/kg twice daily |
| 4 kg |
28 mg (0.3 ml) twice daily |
84 mg (0.85 ml) twice daily |
| 5 kg |
35 mg (0.35 ml) twice daily |
105 mg (1.05 ml) twice daily |
| 7 kg |
49 mg (0.5 ml) twice daily |
147 mg (1.5 ml) twice daily |
Method of using the oral solution
Dosing is performed using the measuring syringe supplied in the package. The syringe has a nominal capacity of 5 mL (corresponds to 500 mg of levetiracetam) with 0.1 mL graduations (corresponds to 10 mg). The measured dose should be diluted in a glass of water (200 mL) or in a feeding bottle.
Dosing the solution using the measuring syringe:
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Children.
Logufen® oral solution can be prescribed to children aged 1 month and older. The drug is not recommended for use in children under 1 month of age due to lack of data on safety and efficacy. The safety of the drug as monotherapy has not been established in children and adolescents under 16 years of age.
Overdose.
Symptoms
In cases of levetiracetam overdose, somnolence, agitation, aggression, respiratory depression, impaired consciousness, and coma have been observed.
Treatment
In case of acute overdose, gastric lavage or induction of emesis is necessary. 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 provided is based on a pooled analysis of data from placebo-controlled clinical trials. These data are supplemented by the use of levetiracetam in appropriate extended open-label studies, as well as post-marketing experience. The safety profile of levetiracetam is generally similar across different age groups (adults and children) when used for the various approved indications in epilepsy.
Adverse reactions reported in clinical trials (in adults, adolescents, children, and infants from 1 month of age) and during the post-marketing period are listed in Table 5 by system organ class and frequency category. Frequency is defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), and very rare (<1/10,000).
Table 5
| MedDRA system organ classes |
Frequency of adverse reactions |
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| very common |
common |
uncommon |
rare |
very rare |
|
| Infections and infestations |
Naso- pharyngitis |
Infections |
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| Blood and lymphatic system disorders |
Thrombocytopenia, leukopenia |
Neutropenia, pancytopenia, agranulocytosis |
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| Immune system disorders |
Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), hypersensitivity (including angioedema and anaphylaxis) |
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| Metabolism and nutrition disorders |
Anorexia |
Weight increased, weight decreased |
Hypnatremia |
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| Psychiatric disorders |
Depression, hostility/aggression, anxiety, insomnia, |
Suicide attempt, |
Suicide, personality disorders, abnormal thinking, delirium |
Obsessive-compulsive disorders** |
|
| Nervous system disorders |
Somnolence, headache |
Seizures, balance disorder, dizziness, lethargy, tremor |
Amnesia, memory impairment, ataxia, coordination disorder, paraesthesia, attention disorders |
Hyperkinesia, dyskinesia, choreoathetosis, gait disturbance, encephalopathy, seizure exacerbation, neuroleptic malignant syndrome* |
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| Eye disorders |
Diplopia, blurred vision |
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| Ear and labyrinth disorders |
Vertigo |
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| Cardiac disorders |
QT interval prolongation on electrocardiogram |
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| Respiratory, thoracic and mediastinal disorders |
Cough |
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| Gastrointestinal disorders |
Diarrhea, dyspepsia, nausea, vomiting, abdominal pain |
Pancreatitis |
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| Hepatobiliary disorders |
Liver function test abnormalities |
Hepatitis, hepatic failure |
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| Renal and urinary disorders |
Acute kidney injury |
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| Skin and subcutaneous tissue disorders |
Rash |
Exfoliative dermatitis, pruritus, alopecia |
Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme |
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| Musculoskeletal and connective tissue disorders |
Myalgia, muscle weakness |
Rhabdomyolysis and elevated creatine phosphokinase in blood* |
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| General disorders |
Asthenia/fatigue |
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| Injury, poisoning and procedural complications |
Injuries |
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*The prevalence is significantly higher in Japanese patients compared to non-Japanese patients.
**During post-marketing surveillance, very rare cases of development of obsessive-compulsive disorders (OCD) have been observed in patients with a history of OCD or psychiatric disorders.
Description of selected adverse reactions
The risk of anorexia increases when levetiracetam is used concomitantly with topiramate.
In cases of alopecia, hair regrowth was observed in some instances after discontinuation of levetiracetam.
In cases of pancytopenia, bone marrow suppression was observed in some instances.
Cases of encephalopathy typically occurred early in treatment (from several days to several months) and were reversible upon discontinuation of treatment.
Children
Overall, 190 patients aged 1 month to 4 years received levetiracetam treatment in placebo-controlled and open-label add-on studies. Of these, 60 patients received levetiracetam in placebo-controlled studies. A total of 645 patients aged 4–16 years received levetiracetam treatment in placebo-controlled and open-label add-on studies, with 233 of these patients receiving levetiracetam in placebo-controlled studies. Data from both age groups were supplemented with post-marketing experience.
Additionally, 101 infants under 12 months of age received treatment in a post-marketing safety study. No new safety data regarding the use of levetiracetam in infants under 12 months of age with epilepsy were obtained.
The adverse reaction profile of levetiracetam is generally similar across different age groups and all approved epilepsy indications. Safety results from placebo-controlled clinical trials in children were consistent with the safety profile of levetiracetam in adults, except for behavioral and psychiatric adverse reactions, which were more frequent in children than in adults. In children 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.
In a double-blind, placebo-controlled safety study in children designed to demonstrate non-inferiority, the effects of levetiracetam on cognitive and neuropsychological parameters were evaluated in children aged 4 to 16 years with partial seizures. Logufen® did not differ from placebo in terms of change from baseline in attention and memory assessed by the Leiter-R scale and total memory score in the per-protocol population. Results related to behavioral and emotional functions indicated worsening in patients treated with levetiracetam, particularly in aggressive behavior, as assessed systematically and using validated tools (CBCL – Achenbach Child Behavior Checklist). However, in patients receiving levetiracetam during a long-term open-label follow-up study, no overall worsening of behavioral and emotional functions was observed on average, 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 and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life.
2 years.
Storage conditions.
Store at temperatures not exceeding 25 °C in the original packaging.
Keep out of reach of children.
After first opening of the bottle, the product should be stored for no more than 7 months.
Packaging.
200 ml in a glass bottle with a tamper-evident cap; 200 ml in a glass bottle with a child-resistant cap. Each bottle is packaged in a cardboard box with a 5 ml dosing syringe and a syringe adapter.
Prescription status.
Prescription only.
Manufacturer.
KUSUM PHARM LLC.
Manufacturer’s location and address of its business operations.
54 Skryabina Street, Sumy, Sumy region, 40020, Ukraine.
or
Manufacturer.
GLEDPHARM LTD LLC.
Manufacturer’s location and address of its business operations.
54 Davydovskoho Hryhorii Street, Sumy, Sumy region, 40020, Ukraine.