Levetiracetam TilloMed

SUMMARY OF PRODUCT CHARACTERISTICS
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1. NAME OF THE MEDICINAL PRODUCT

Levetiracetam Tillomed 100 mg/ml concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 100 mg of levetiracetam.
Each 5 ml vial contains 500 mg of levetiracetam.
Excipient with known effect:
Each vial contains 17.13 mg of sodium.
For the complete list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Concentrate for solution for infusion
Clear, colourless liquid.
pH: from 5.00 to 6.00
Osmolarity: not more than 1150 mOsmol/kg

4. CLINICAL INFORMATION

4.1. Therapeutic Indications
Levetiracetam is indicated as monotherapy in the treatment of partial-onset seizures with or without
secondary generalization in adults and adolescents from the age of 16 years with newly diagnosed
epilepsy.
Levetiracetam is indicated as adjunctive therapy

• in the treatment of partial-onset seizures with or without secondary generalization in adults, adolescents and children from 4 years of age with epilepsy
• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy
• in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalized Epilepsy.

Levetiracetam concentrate for solution for infusion represents an alternative for patients when oral
therapy is temporarily not feasible.
4.2. Posology and Method of Administration
Posology
Levetiracetam treatment may be initiated either intravenously or orally.
Switching between oral and intravenous routes can be done directly without titration.
The total daily dose and frequency of administration should be maintained.
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Partial-onset seizures
The recommended dosage for monotherapy (from age 16 years) and for adjunctive therapy is the same as indicated below.
All indications
Adults (≥18 years) and adolescents (12 to 17 years) weighing ≥50 kg
The initial therapeutic dose is 500 mg twice daily. This dose may be used from the first day of treatment. However, a lower initial dose of 250 mg twice daily may be prescribed at the physician’s discretion, considering the balance between seizure reduction and potential adverse effects. This may be increased to 500 mg twice daily after two weeks.
Based on clinical response and tolerability, the daily dose may be increased up to a maximum of 1500 mg twice daily. Dose adjustments may be made in increments or decrements of 250 mg or 500 mg twice daily, every two to four weeks.
Adolescents (12 to 17 years) weighing <50 kg and children from 4 years of age
The physician must prescribe the most appropriate pharmaceutical form, formulation, and dosage based on weight, age, and required dose. For dosage adjustments based on weight, refer to the section Pediatric Population.
Duration of treatment
There is no experience with intravenous administration of levetiracetam for periods exceeding 4 days.
Discontinuation of treatment
If levetiracetam treatment needs to be discontinued, gradual withdrawal is recommended (e.g., in adults and adolescents weighing >50 kg: reduce by 500 mg twice daily at intervals of two to four weeks; in children and adolescents weighing <50 kg: dose reduction should not exceed 10 mg/kg twice daily every two weeks).
Special populations
Elderly (aged 65 years and older)
Dosage adjustment is recommended in elderly patients with reduced renal function (see “Renal impairment” below).
Renal impairment
The daily dose should be individualized based on renal function.
For adult patients, refer to the table below and adjust dosage accordingly. To use this dosing table, the patient’s creatinine clearance (CLcr) in ml/min must be assessed. CL (ml/min) can be calculated from serum creatinine (mg/dl) using the following formula for adults and adolescents weighing ≥50 kg:
[140 - age (years)] x weight (kg)
CL (ml/min) = -------------------------------------- (x 0.85 in women)
72 x serum creatinine (mg/dl)
Furthermore, CL is adjusted for body surface area (BSA) as follows:
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CL (ml/min)
CL (ml/min/1.73 m²) = -------------------------------- x 1.73
BSA of subject (m²)
Dosage adjustment for adult and adolescent patients weighing >50 kg with impaired renal function
Group Creatinine clearance Dose and frequency of
(ml/min/1.73 m²) administration
Normal ≥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
Patients with end-stage renal -- 500 to 1000 mg once daily
disease undergoing dialysis
A loading dose of 750 mg is recommended on the first day of levetiracetam treatment.
An additional supplemental dose of 250 to 500 mg is recommended after dialysis.
For children with renal impairment, levetiracetam dosage should be adjusted based on renal function, as levetiracetam clearance is correlated with renal function. This recommendation is based on a study conducted in adult patients with renal impairment.
In young adolescents and children, CL (ml/min/1.73 m²) can be estimated from serum creatinine (mg/dl) using the following formula (Schwartz formula):
Height (cm) x ks
CL (ml/min/1.73 m²) = -------------------------------------------
Serum creatinine (mg/dl)
ks = 0.55 in children under 13 years of age and adolescent females; ks = 0.7 in adolescent males
Dosage adjustment for children and adolescents weighing <50 kg with impaired renal function:

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A loading dose of 15 mg/kg (0.15 ml/kg) is recommended on the first day of treatment with levetiracetam.
After dialysis, a supplementary dose of 5 to 10 mg/kg (0.05 to 0.10 ml/kg) is recommended.

Hepatic impairment
No dosage adjustment is required in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, creatinine clearance may underestimate the degree of renal impairment. Therefore, when creatinine clearance is <60 ml/min/1.73 m², a 50% reduction of the daily maintenance dose is recommended.

Paediatric population
The physician must prescribe the most appropriate pharmaceutical form, route of administration, and dosage based on age, weight, and required dose.

Monotherapy
The safety and efficacy of levetiracetam used as monotherapy in children and adolescents under 16 years of age have not been established.
No data are available.

Adolescents (16 and 17 years of age) weighing equal to or greater than 50 kg with partial-onset seizures with or without secondary generalisation in newly diagnosed epilepsy
Refer to the section above on Adults (≥18 years) and adolescents (12 to 17 years) weighing equal to or greater than 50 kg.

Adjunctive therapy for children aged 4 to 11 years and adolescents (12 to 17 years) weighing less than 50 kg
The initial therapeutic dose is 10 mg/kg twice daily.
Based on clinical response and tolerability, the dose may be increased up to 30 mg/kg twice daily. Dosage adjustments should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used for all indications.

The dose in children weighing equal to or greater than 50 kg is the same as that for adults for all indications.
Refer to the section above on Adults (≥18 years) and adolescents (12 to 17 years) weighing equal to or greater than 50 kg for all indications.

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Recommended dose for children and adolescents:

Children weighing 25 kg or less should preferably start treatment with
levetiracetam 100 mg/ml oral solution.
The dose in children and adolescents weighing 50 kg or more is the same as in adults.
Adjunctive therapy in infants and children under 4 years of age
The safety and efficacy of Levetiracetam concentrate for infusion solution in infants and children
under 4 years of age have not been established.
Available data are reported in sections 4.8, 5.1 and 5.2, but no dosage recommendations can be made.
Method of administration
Levetiracetam concentrate for infusion solution is for intravenous use only, and the recommended dose
must be diluted in at least 100 ml of a compatible diluent and administered intravenously by 15-minute
intravenous infusion (see section 6.6).
4.3. Contraindications
Hypersensitivity to the active substance or to other pyrrolidone derivatives or to any of the excipients
listed in section 6.1.
4.4. Special warnings and precautions for use
Renal impairment
Administration of levetiracetam in patients with renal impairment may require dose adjustment. In
patients with severely impaired hepatic function, renal function should be assessed before determining
the dosage (see section 4.2).
Acute renal injury
The use of levetiracetam has very rarely been associated with acute renal injury, with onset ranging from
a few days to several months.
Blood cell count
Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leukopenia, thrombocytopenia,
and pancytopenia) have been reported in association with levetiracetam administration, usually at the
beginning of treatment. A complete blood count is recommended in patients presenting with marked
weakness, fever, recurrent infections, or coagulation disorders (section 4.8).
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Suicidal behaviour
Suicide, suicide attempts, suicidal ideation, and suicidal behaviour have been reported in patients
treated with antiepileptic drugs (including levetiracetam). A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs showed a slight increase in the risk of suicidal ideation and behaviour. The mechanism of this risk is unknown.
Therefore, patients should be monitored for the emergence of signs of depression and/or suicidal
ideation and behaviour, and appropriate treatment should be considered. Patients (and caregivers)
should be advised that if signs of depression and/or suicidal ideation or behaviour emerge, medical
advice must be sought immediately.
Abnormal and aggressive behaviours
Levetiracetam may cause psychiatric symptoms and abnormal behaviours including irritability and
aggressiveness. Patients treated with levetiracetam should be monitored for the development of
psychiatric signs indicating significant mood and/or personality changes. If such changes occur, dose
modification or gradual discontinuation of treatment should be considered. In case of treatment
discontinuation, reference should be made to section 4.2.
Worsening of seizures
As with other types of antiepileptic drugs, levetiracetam may rarely worsen the frequency or severity of
seizures. This paradoxical effect has been reported mainly within the first month after starting
levetiracetam treatment or increasing the dose, and has been reversible upon discontinuation or dose
reduction. Patients should be warned to consult their physician immediately if their epilepsy worsens.
Lack of efficacy or worsening of seizures has been reported, for example, in patients with epilepsy
associated with mutations in the gene encoding the alpha-8 subunit of the voltage-dependent sodium
channel (SCN8A).
Prolongation of QT interval on electrocardiogram
Rare cases of QT interval prolongation on ECG have been observed during post-marketing surveillance. Levetiracetam should be used with caution in patients with QTc interval prolongation, in patients treated concomitantly with drugs affecting the QTc interval, or in patients with relevant pre-existing cardiac conditions or electrolyte imbalances.
Paediatric population
Available data in children do not indicate an effect on growth and puberty. However, the long-term
effects on learning, intelligence, growth, endocrine function, puberty, and reproductive potential in
children are unknown.
Excipients
This medicinal product contains 19.1 mg of sodium per vial (5 ml), equivalent to 0.796% of the
maximum daily intake recommended by the WHO, which corresponds to 2 g of sodium for an adult.
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4.5. Interactions with other medicinal products and other forms of interaction
Antiepileptic drugs
Data from pre-marketing clinical studies in adults indicate that levetiracetam does not influence serum
concentrations of existing antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital,
lamotrigine, gabapentin, and primidone), and that these antiepileptics do not influence the
pharmacokinetics of levetiracetam.
As in adults, in paediatric patients receiving doses up to 60 mg/kg/day of levetiracetam, there is no
evidence of clinically significant interactions with other drugs.
A retrospective evaluation of pharmacokinetic interactions in children and adolescents with epilepsy
(aged 4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not
affect steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20% higher clearance of levetiracetam in children taking antiepileptic drugs with enzyme-inducing effects. Dose adjustment is not required.
Probenecid
Probenecid (500 mg four times daily), an agent blocking renal tubular secretion, was shown to inhibit
the renal clearance of the primary metabolite but not of levetiracetam. However, the concentration of
this metabolite remains low.
Methotrexate
Concomitant administration of levetiracetam and methotrexate has been reported to decrease
methotrexate clearance, resulting in increased or prolonged blood methotrexate concentrations up to
potentially toxic levels. Blood levels of methotrexate and levetiracetam should be closely monitored in
patients treated with both agents.
Oral contraceptives and other pharmacokinetic interactions
Levetiracetam 1000 mg daily did not affect the pharmacokinetics of oral contraceptives (ethinylestradiol
and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not altered.
Levetiracetam 2000 mg daily did not affect the pharmacokinetics of digoxin and warfarin; prothrombin
times were not altered. Concomitant administration of digoxin, oral contraceptives, and warfarin did
not affect the pharmacokinetics of levetiracetam.
Alcohol
No data are available on interactions between levetiracetam and alcohol.
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4.6. Fertility, pregnancy and lactation
Women of childbearing potential
Specialist advice should be sought for women of childbearing potential. Treatment with levetiracetam
should be reconsidered when a woman is planning pregnancy. As with all antiepileptic drugs, abrupt
discontinuation of levetiracetam should be avoided, as this could lead to the occurrence of breakthrough
seizures, which could have serious consequences for both the woman and the unborn child. Monotherapy should always be preferred when possible, since treatment with multiple antiepileptic drugs may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the antiepileptics used in combination.
Pregnancy
A large amount of post-marketing data from pregnant women exposed to levetiracetam as monotherapy
(more than 1800 cases, with exposure during the first trimester in over 1500) does not suggest an
increased risk of major congenital malformations. Evidence on the neurological development of children
exposed to levetiracetam monotherapy in utero is limited. However, recent epidemiological studies
(in approximately 100 children) do not suggest an increased risk of neurodevelopmental disorders or
delays.
Levetiracetam may be used during pregnancy if, after careful evaluation, it is considered clinically
necessary. In such cases, the lowest effective dose is recommended.
Physiological changes occurring during pregnancy may affect plasma concentrations of levetiracetam.
During pregnancy, a reduction in plasma concentrations of levetiracetam has been observed. This
reduction is more pronounced during the third trimester (up to 60% of the pre-pregnancy baseline
concentration). Adequate clinical management of pregnant women treated with levetiracetam must be
ensured.
Breast-feeding
Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended.
However, if treatment with levetiracetam becomes necessary during breast-feeding, the risk-benefit
balance of treatment should be evaluated, taking into account the importance of breast-feeding.
Fertility
No impact on fertility was observed in animal studies (see section 5.3). Clinical data are not available;
the potential risk in humans is unknown.
4.7. Effects on ability to drive and use machines
Levetiracetam has a low or moderate influence on the ability to drive and use machines. Due to possible
individual differences in sensitivity, some patients may experience somnolence or other central nervous
system-related symptoms, particularly at the beginning of treatment or following a dose increase.
Therefore, caution is recommended for patients engaged in activities requiring high concentration, such
as driving vehicles or operating
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machinery. Patients should be advised not to drive or operate machinery until it is established that their
ability to perform these activities is not impaired.
4.8. Undesirable effects
Summary of safety profile
The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue,
and dizziness. The adverse reaction profile presented below is based on the analysis of pooled placebo-controlled clinical trials across all studied indications, involving a total of 3,416 patients treated with levetiracetam. These data are supplemented by data from open-label extension studies and post-marketing experience. The safety profile of levetiracetam is generally similar across different age groups (adult and paediatric patients) and approved indications for the treatment of epilepsy. Since exposure to intravenous levetiracetam is limited and since oral and intravenous formulations are bioequivalent, safety information for intravenous levetiracetam will be based on the use of oral levetiracetam.
Table of adverse reactions
Adverse reactions reported in clinical trials (adults, adolescents, children, and infants over 1 month of
age) and in post-marketing experience are listed in the table below by system organ class and frequency.
Adverse reactions are listed in decreasing order of severity, and their frequency is defined as follows:
very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000).

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See the section “Description of selected adverse reactions”.
During post-marketing surveillance, very rare cases of development of obsessive-compulsive disorders (OCD) have been observed in patients with a previous history of OCD or psychiatric disorders.
The prevalence is significantly higher in Japanese patients compared to non-Japanese patients.
Description of selected adverse reactions
Multi-organ hypersensitivity reactions
Multi-organ hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms, DRESS) have been reported rarely in patients treated with levetiracetam. Clinical manifestations may develop from 2 to 8 weeks after the start of therapy. These reactions may vary in presentation but typically include fever, rash, facial swelling, lymphadenopathy, hematological abnormalities, and may be associated with involvement of multiple organ systems, particularly the liver. If multi-organ hypersensitivity is suspected, levetiracetam should be discontinued.
The risk of anorexia is higher when levetiracetam is administered concomitantly with topiramate.
In numerous cases of alopecia, recovery has been observed after discontinuation of levetiracetam treatment.
In some cases of pancytopenia, bone marrow suppression has been identified.
Cases of encephalopathy have occurred, generally at the beginning of treatment (from a few days to several months), and have been reversible upon discontinuation of treatment.
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Paediatric population
In patients aged 1 month to less than 4 years, a total of 190 patients were treated with levetiracetam in placebo-controlled studies and open-label extension studies. Sixty of these patients were treated with levetiracetam in placebo-controlled studies. In patients aged between 4 and 16 years, a total of 645 patients were treated with levetiracetam in placebo-controlled studies and open-label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both of these paediatric age groups, these data are supplemented with post-marketing experience regarding the use of levetiracetam.
Additionally, 101 infants under 12 months of age were enrolled in a post-authorisation safety study. No new safety concerns for levetiracetam were identified in infants under 12 months of age with epilepsy.
The adverse reaction profile of levetiracetam is generally similar across different age groups and approved indications in the treatment of epilepsy. In placebo-controlled clinical trials, safety findings in paediatric patients were consistent with the safety profile of levetiracetam in adults, except for behavioural and psychiatric adverse reactions, which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affective lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age groups or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and abnormal coordination (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile.
A paediatric safety study, conducted under a non-inferiority design, double-blind and placebo-controlled, evaluated the cognitive and neuropsychological effects of levetiracetam in children aged 4 to 16 years with partial-onset seizures. Levetiracetam was shown to be not different (non-inferior) compared to placebo regarding change from baseline in scores on the "Attention and Memory" subtests of the Leiter-R scale (Memory Screen Composite score) in the per-protocol population. Results related to behavioural and emotional functions indicated worsening, in patients treated with levetiracetam, of aggression measured in a standardized and systematic manner using a validated instrument (CBCL – Achenbach Child Behaviour Checklist).
However, subjects who received levetiracetam in the subsequent long-term open-label follow-up study did not show, on average, worsening of their behavioural and emotional functions; in particular, assessments of aggressive behaviour did not worsen from baseline.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization of the medicinal product is important, as it allows continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the website: http://www.agenziafarmaco.gov.it/content/come-segnalare-una-sospetta-reazione-avversa.
4.9. Overdose
Symptoms
Somnolence, agitation, aggression, reduced level of consciousness, respiratory depression, and coma have been observed in cases of levetiracetam overdose.
Treatment of overdose
There is no specific antidote for levetiracetam. Management of levetiracetam overdose should be symptomatic and may include haemodialysis. The elimination efficiency by dialysis is 60% for levetiracetam and 74% for its primary metabolite.
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5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties
Pharmacotherapeutic category: antiepileptics, other antiepileptics, ATC code: N03AX14.
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic agents.

Mechanism of Action
The mechanism of action of levetiracetam has not yet been fully elucidated. In vitro and in vivo experiments suggest that levetiracetam does not alter basic cellular characteristics or normal neurotransmission.

In vitro studies show that levetiracetam acts on intraneuronal Ca levels by partially inhibiting N-type Ca currents and reducing Ca release from intraneuronal storage sites. In addition, it partially reverses the reduction, induced by zinc and β-carbolines, of GABA- and glycine-induced currents. In vitro studies have also demonstrated that levetiracetam binds to a specific site in rodent brain tissue. This binding site is synaptic vesicle protein 2A (SV2A), which is believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and its analogues show a degree of affinity for binding to synaptic vesicle protein 2A that correlates with the potency of their antiepileptic protection in the audiogenic seizure model in mice. This finding suggests that the interaction between levetiracetam and synaptic vesicle protein 2A appears to play a role in the antiepileptic mechanism of action of the medicinal product.

Pharmacodynamic Effects
Levetiracetam provides protective effects across a broad spectrum of animal models of partial and primary generalized epilepsy, without exerting a pro-convulsant effect. The primary metabolite is inactive. In humans, activity under conditions of both partial and generalized epilepsy (epileptiform discharges/photoparoxysmal response) has confirmed the broad pharmacological profile of levetiracetam.

Clinical Efficacy and Safety

Adjunctive therapy in the treatment of partial-onset seizures, with or without secondary generalization, in adults, adolescents, and children from 4 years of age with epilepsy

The efficacy of levetiracetam in adults has been demonstrated in three double-blind, placebo-controlled studies with doses of 1000 mg, 2000 mg, or 3000 mg/day, divided into two administrations, with a treatment duration of up to 18 weeks. In a pooled analysis, the percentage of patients achieving a reduction in weekly frequency of partial-onset seizures of at least 50% compared to baseline during the stable-dose treatment period (12–14 weeks) was 27.7%, 31.6%, and 41.3% for patients treated with 1000, 2000, or 3000 mg of levetiracetam, respectively, and 12.6% for patients treated with placebo.

Paediatric population
The efficacy of levetiracetam in paediatric patients (4 to 16 years of age) has been demonstrated in one double-blind, placebo-controlled study involving 198 patients, with a treatment duration of 14 weeks. In this study, patients received levetiracetam at a fixed dose of 60 mg/kg/day (administered in two daily doses).

In this study, 44.6% of patients treated with levetiracetam and 19.6% of patients treated with placebo achieved, compared to baseline, a reduction in weekly frequency of partial-onset seizures of at least 50%. With continued long-term treatment, 11.4% of patients remained seizure-free for at least 6 months and 7.2% remained seizure-free for at least 1 year.
Thirty-five infants under one year of age, of whom only 13 were under 6 months of age, with partial-onset seizures were included in placebo-controlled clinical trials.

Monotherapy in the treatment of partial-onset seizures, with or without secondary generalization, in patients from 16 years of age with newly diagnosed epilepsy

The efficacy of levetiracetam as monotherapy has been demonstrated in a double-blind, parallel-group, non-inferiority comparative study versus controlled-release carbamazepine (CR) in 576 patients aged 16 years or older with newly or recently diagnosed epilepsy. Patients had to experience only unprovoked partial seizures or generalized tonic-clonic seizures. Patients were randomized to receive either carbamazepine CR 400–1200 mg/day or levetiracetam 1000–3000 mg/day based on response, with treatment duration of up to 121 weeks.

Seizure freedom for a period of 6 months was achieved in 73.0% of patients treated with levetiracetam and in 72.8% of patients treated with carbamazepine CR; the absolute difference corrected between treatments was 0.2% (95% CI: -7.8 to 8.2). More than half of the subjects remained seizure-free for 12 months (56.6% and 58.5% of subjects treated with levetiracetam and carbamazepine CR, respectively).

In a study reflecting clinical practice, concomitant antiepileptic treatment could be discontinued in a limited number of patients who responded to adjunctive therapy with levetiracetam (36 out of 69 adult patients).

Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy

The efficacy of levetiracetam has been demonstrated in a double-blind, placebo-controlled study of 16 weeks' duration in patients aged 12 years or older with idiopathic generalized epilepsy and myoclonic seizures in different syndromes. The majority of patients had juvenile myoclonic epilepsy.

In this study, the dose of levetiracetam was 3000 mg/day, administered in two separate doses.
58.3% of patients treated with levetiracetam and 23.3% of patients treated with placebo experienced at least a 50% reduction in the number of days per week with myoclonic seizures. Following continued long-term treatment, 28.6% of patients remained free from myoclonic seizures for at least 6 months and 21.0% remained free from myoclonic seizures for at least 1 year.

Adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy

The efficacy of levetiracetam has been demonstrated in a 24-week, double-blind, placebo-controlled study that included adults, adolescents, and a limited number of children with idiopathic generalized epilepsy and primary generalized tonic-clonic seizures (PGTC) in different syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with generalized tonic-clonic seizures upon awakening). In this study, the dose of levetiracetam was 3000 mg/day for adults and adolescents, or 60 mg/kg/day for children, administered in two separate doses.

72.2% of patients treated with levetiracetam and 45.2% of patients treated with placebo experienced a reduction in weekly frequency of PGTC seizures of at least 50%. Following continued long-term treatment, 47.4% of patients remained free from tonic-clonic seizures for at least 6 months and 31.5% remained free from tonic-clonic seizures for at least 1 year.

5.2. Pharmacokinetic Properties
The pharmacokinetic profile has been described following oral administration. A single dose of 1500 mg of levetiracetam diluted in 100 ml of a compatible diluent and administered intravenously over 15 minutes is bioequivalent to 1500 mg of levetiracetam administered orally as three 500 mg tablets.

Intravenous administrations of doses up to 4000 mg diluted in 100 ml of 0.9% sodium chloride infused over 15 minutes and doses up to 2500 mg diluted in 100 ml of 0.9% sodium chloride infused over more than 5 minutes have been evaluated. Pharmacokinetic and safety profiles did not reveal any safety concerns.

Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and inter-individual variability. There is no change in clearance after repeated administration. The time-independent pharmacokinetic profile of levetiracetam has also been confirmed following a 1500 mg intravenous infusion for 4 days with two daily administrations.

There is no evidence of any relevant circadian, gender, or racial variability. The pharmacokinetic profile is comparable in healthy volunteers and patients with epilepsy.

Adults and Adolescents

Distribution
The peak plasma concentration (C_max) observed in 17 subjects following a single intravenous dose of 1500 mg infused over 15 minutes was 51 ± 19 μg/ml (arithmetic mean ± standard deviation).

No data on tissue distribution in humans are available.
Neither levetiracetam nor its primary metabolite binds significantly to plasma proteins (<10%).
The volume of distribution of levetiracetam ranges approximately from 0.5 to 0.7 l/kg, a value close to the total body water volume.

Metabolism
Levetiracetam is not extensively metabolized in humans. The main metabolic pathway (24% of the dose) is enzymatic hydrolysis of the acetamide group. The formation of the primary metabolite, ucb L057, is not mediated by hepatic cytochrome P450 isoenzymes. Hydrolysis of the acetamide group has been measurable in numerous tissues, including blood cells. The 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 ring (0.9% of the dose).
Other unknown components accounted for only 0.6% of the dose.

In vivo, no enantiomeric interconversion has been observed for either levetiracetam or its primary metabolite.

In vitro, levetiracetam and its primary metabolite showed no inhibition of the activities of major human hepatic cytochrome P450 isoenzymes (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1, and 1A2), glucuronosyl transferases (UGT1A1 and UGT1A6), or epoxide hydrolase. Furthermore, levetiracetam does not influence the in vitro glucuronidation of valproic acid.

In cultures of human hepatocytes, levetiracetam had minimal or no effect on CYP1A2, SULT1E1, or UGT1A1. Levetiracetam caused slight induction of CYP2B6 and CYP3A4. In vitro and in vivo data on interactions with oral contraceptives, digoxin, and warfarin indicate that no significant enzymatic induction is expected in vivo. Therefore, interactions between levetiracetam and other substances, or vice versa, are unlikely.

Elimination
The plasma half-life in adults is 7±1 hours and does not change with dose, route of administration, or repeated administration. The mean total body clearance is 0.96 ml/min/kg.

The main route of excretion is urinary, accounting for the elimination of approximately 95% of the administered dose (about 93% of the dose is excreted within 48 hours).
Faecal elimination accounts for only 0.3% of the dose.

Cumulative urinary excretion of levetiracetam and its primary metabolite accounts for 66% and 24% of the dose, respectively, within the first 48 hours.

The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg, respectively, indicating that levetiracetam is excreted via glomerular filtration followed by tubular reabsorption, and that the primary metabolite is also excreted via active tubular secretion in addition to glomerular filtration. The elimination of levetiracetam is correlated with creatinine clearance.

Elderly
In the elderly, the half-life is increased by approximately 40% (from 10 to 11 hours). This is due to reduced renal function in this population (see section 4.2).

Renal Impairment
The apparent total clearance of both levetiracetam and its primary metabolite is correlated with creatinine clearance. Therefore, in patients with moderate and severe renal impairment, adjustment of the daily maintenance dose of levetiracetam is recommended based on creatinine clearance (see section 4.2).

In anuric adult subjects with end-stage renal disease, the half-life was approximately 25 hours and 3.1 hours during the interdialytic and dialysis periods, respectively. The fraction of levetiracetam removed during a typical 4-hour dialysis session was 51%.

Hepatic Impairment
In subjects with mild to moderate hepatic impairment, no significant change in levetiracetam clearance was observed. In the majority of subjects with severe hepatic impairment, levetiracetam clearance was reduced by more than 50% due to concomitant renal impairment (see section 4.2).

Paediatric Population

Children (4 to 12 years)
Pharmacokinetic investigations following intravenous administration have not been performed in paediatric patients. However, based on the pharmacokinetic characteristics of levetiracetam, pharmacokinetics in adults after intravenous administration, and pharmacokinetics in children after oral administration, exposure (AUC) of levetiracetam in paediatric patients aged 4 to 12 years is expected to be similar after intravenous and oral administration.

Following a single oral dose (20 mg/kg) in children (6 to 12 years) with epilepsy, the half-life of levetiracetam was 6.0 hours. The apparent clearance corrected for body weight was approximately 30% higher than in adults with epilepsy.

Following repeated oral administration (20 to 60 mg/kg/day) in epileptic children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentration was observed between 0.5 and 1.0 hours after dosing. Linear and dose-proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately 5 hours. The apparent total body clearance was 1.1 ml/min/kg.

5.3. Preclinical Safety Data
Non-clinical data reveal no special risk for humans based on conventional studies of pharmacological safety, genotoxicity, and carcinogenic potential.

Adverse events not observed in clinical studies but reported in rats and, to a lesser extent, in mice, at exposure levels similar to those in humans and with possible relevance to clinical use, included hepatic changes and adaptive response indicators such as increased body weight, centrilobular hypertrophy, fatty infiltration, and elevated hepatic enzymes in plasma.

No adverse effects on male or female fertility or reproductive capacity were observed in rats at doses up to 1800 mg/kg/day (6 times the maximum recommended human daily dose (MRHD) based on mg/m² or exposure), in either parental or F1 generations.

Two embryofetal development (EFD) studies were conducted in rats at doses of 400, 1200, and 3600 mg/kg/day. At 3600 mg/kg/day, in only one of the two EFD studies, a slight reduction in fetal weight was observed, associated with a marginal increase in skeletal variations/minor anomalies. No effect on embryonic mortality was observed, nor was there an increase in the incidence of malformations. The NOAEL (No Observed Adverse Effect Level) was 3600 mg/kg/day for pregnant rat dams (12 times the MRHD based on mg/m²) and 1200 mg/kg/day for fetuses.

Four embryofetal development studies were conducted in rabbits using doses of 200, 600, 800, 1200, and 1800 mg/kg/day. The dose of 1800 mg/kg/day induced marked maternal toxicity and reduced fetal weight, associated with a higher incidence of fetuses with cardiovascular/skeletal anomalies. The NOAEL was <200 mg/kg/day for pregnant females and 200 mg/kg/day for fetuses (equivalent to the MRHD based on mg/m²).

One peri- and post-natal development study was conducted in rats with levetiracetam doses of 70, 350, and 1800 mg/kg/day. The NOAEL was ≥1800 mg/kg/day for F0 females and F1 generation regarding survival, growth, and development up to weaning (6 times the MRHD based on mg/m²).

Studies in neonatal and young animals (rats and dogs) have shown that no adverse effects occur in any standard developmental or maturation endpoints at doses up to 1800 mg/kg/day (6–17 times the MRHD based on mg/m²).

6. PHARMACEUTICAL INFORMATION

6.1. List of excipients
Sodium chloride
Sodium acetate trihydrate
Glacial acetic acid
Water for injections

6.2. Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3. Shelf life
Unopened vial: 3 years.
Chemical and physical in-use stability has been demonstrated for 24 hours at 25 °C ± 2 °C (room temperature) in polypropylene vials and flexible PVC bags.
From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, the in-use storage times and conditions prior to use are the responsibility of the user and normally should not exceed 24 hours at 2–8 °C, unless dilution has taken place under validated aseptic and controlled conditions.

6.4. Special precautions for storage
This medicinal product requires no special storage conditions.
For storage conditions of the medicinal product after dilution, see section 6.3.

6.5. Nature and contents of container
5 ml Type I glass vial with a bromobutyl rubber stopper and an aluminium crimp cap.
The vials contain 5 ml of concentrate for solution for infusion and are packaged in a cardboard box.
Each box contains 1 or 10 vials.
Not all pack sizes may be marketed.

6.6. Special precautions for disposal and handling
Refer to Table 1 for the recommended preparation and administration of Levetiracetam concentrate for solution for infusion to achieve a total daily dose of 500 mg, 1000 mg, 2000 mg, or 3000 mg given in two divided doses.
Table 1. Preparation and administration of levetiracetam concentrate for solution for infusion

This medicinal product is for single use only; any residual solution must be discarded.
Levetiracetam concentrate for infusion solution has been shown to be physically compatible and chemically stable for at least 24 hours when mixed with the following diluents and stored in PVC bags at a controlled room temperature of 15–25°C.
Diluents:

• Sodium chloride 9 mg/ml (0.9%) injection
• Lactated Ringer's injection
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• Dextrose 50 mg/ml (5%) injection

Do not use the medicinal product if it contains particulate matter or discoloration.
Unused medicinal product and waste material derived from this medicinal product must be disposed of in accordance with local regulations.

7. MARKETING AUTHORISATION HOLDER

Tillomed Italia S.r.l.
viale Richard 1, Torre A
20143, Milan
Italy

8. MARKETING AUTHORISATION NUMBER(S)

046275018 - “100 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION” 1
5 ML GLASS VIAL
046275020 - “100 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION” 10
5 ML GLASS VIALS

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21/03/2019
Date of most recent renewal: 09/04/2023

10. DATE OF TEXT REVISION

09/2025
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