Keppra

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KEPRA® (Keppra®)

Composition:

Active substance: levetiracetam;

1 ml of solution contains 100 mg of levetiracetam;

Excipients: citric acid monohydrate, ammonium glycyrrhizinate, sodium citrate, methylparaben (E 218), propylparaben (E 216), glycerol 85% (E 422), maltitol liquid (E 965), potassium acesulfame (E 950), grape flavoring additive Firmenich 501040A, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear liquid.

Pharmacotherapeutic group. Antiepileptic drugs. Levetiracetam.

ATC code N03A X14.

Pharmacological Properties.

Pharmacodynamics.

Levetiracetam, the active substance, is a pyrrolidone derivative (S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine-acetamide) and is chemically distinct from known antiepileptic drugs.

Mechanism of action

The mechanism of action of levetiracetam is not fully understood. Based on in vitro and in vivo studies, it is presumed that levetiracetam does not alter the basic characteristics of nerve cells or normal neurotransmission. In vitro studies have shown that levetiracetam affects intraneuronal Ca2+ levels by partially inhibiting Ca2+ influx through N-type calcium 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 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 causing proconvulsant effects. The primary metabolite is inactive.

In humans, the drug's activity has been confirmed for both partial and generalized epileptic seizures (epileptiform discharges/photoparoxysmal response), indicating the broad pharmacological profile of levetiracetam.

Pharmacokinetics.

Levetiracetam is characterized by high solubility and permeability. Its pharmacokinetics are linear and exhibit low inter- and intrasubject variability. After repeated administration, clearance does not change. No significant effects of gender, race, or circadian rhythm on pharmacokinetics have 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 mg/kg body weight. Therefore, monitoring plasma levels of levetiracetam is not necessary.

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 tablet administration and 4 hours after oral solution intake).

Adults and adolescents

Absorption.

Levetiracetam is rapidly absorbed after oral administration. Absolute oral bioavailability is close to 100%. Peak plasma concentrations (Cmax) are reached within 1.3 hours after drug intake. Steady-state levels are achieved within 2 days of twice-daily dosing. Peak concentrations (Cmax) typically reach 31 and 43 µg/mL after a single 1000 mg dose and repeated 1000 mg twice daily, respectively. The extent of absorption is independent of dose and is not altered by food intake.

Distribution.

Data on tissue distribution in humans are lacking. Neither levetiracetam nor its primary metabolite bind significantly to plasma proteins (< 10%). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L/kg, which corresponds to the total body water volume.

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 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 the dose), and the other by opening of the pyrrolidone ring (0.9% of the dose).

Other unidentified components accounted for only 0.6% of the dose.

No interconversion of enantiomers of levetiracetam or its 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, and 1A2), glucuronosyltransferases (UGT1A1 and UGT1A6), or epoxide hydrolase. Levetiracetam also does not inhibit the glucuronidation of valproic acid in vitro.

In human hepatocyte cultures, levetiracetam showed weak or no effect on CYP1A1/2, SULT1E1, or UGT1A1. Levetiracetam caused weak induction of CYP2B6 and CYP3A4. In vitro and in vivo data on interactions with oral contraceptives, digoxin,

and warfarin suggest that significant enzyme induction is not expected under in vivo conditions. Therefore, clinically relevant interactions between levetiracetam and other substances, or vice versa, are unlikely.

Elimination.

The elimination half-life of the drug in plasma in adults is 7±1 hours and does not depend on dose, route of administration, or repeated dosing. Mean total clearance is 0.96 mL/min/kg.

Approximately 95% of the administered dose is excreted in urine (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 is 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 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, the 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, dosage 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 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 4-hour fractionated dialysis session, 51% of levetiracetam is removed.

Hepatic impairment.

In patients with mild to moderate hepatic impairment, no significant changes in levetiracetam clearance were observed. 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) in children with epilepsy (aged 6 to 12 years), the elimination half-life of levetiracetam was 6 hours. Apparent clearance, corrected for body weight, was approximately 30% higher than in adult epilepsy patients. After repeated oral administration (20–60 mg/kg/day) in children with epilepsy (aged 4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentrations were reached within 0.5–1 hour after dosing. Peak concentrations and area under the concentration-time curve increased linearly and were dose-dependent. The elimination half-life was approximately 5 hours; apparent total clearance was 1.1 mL/min/kg.

Infants and children aged 1 month to 4 years.

After a single dose (20 mg/kg) of oral solution 100 mg/mL in children with epilepsy (aged 1 month to 4 years), levetiracetam was rapidly absorbed, with peak plasma concentration observed approximately 1 hour after dosing. Pharmacokinetic parameters indicated 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 indicated a significant correlation between body weight and apparent clearance (clearance increased with increasing body weight) and apparent volume of distribution. Age also influenced both parameters. This effect was more pronounced in younger infants, decreased with age, and was negligible in children around 4 years of age.

Data from both population pharmacokinetic analyses indicated an approximately 20% increase in apparent clearance of levetiracetam when co-administered with enzyme-inducing antiepileptic drugs.

Clinical characteristics.

Indications.

Monotherapy (first-line treatment) 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 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, as well as to any excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Antiepileptic drugs.

Pre-registration clinical trial data in adult patients indicate that levetiracetam does not affect serum concentrations of other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone), and these drugs do not affect the pharmacokinetics of levetiracetam.

There are no data on clinically significant interactions of the medicinal product in pediatric patients, as well as in adults receiving up to 60 mg/kg/day of levetiracetam.

A retrospective 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 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 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 (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 values 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 taking levetiracetam.

Food and alcohol.

The extent of levetiracetam absorption is not affected by food, 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 adjustment of the levetiracetam dosage. In patients with severe hepatic dysfunction, renal function should be assessed prior to initiating treatment (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, typically at the beginning of treatment. Complete blood count monitoring is recommended in patients presenting with significant weakness, fever, recurrent infections, or coagulation disorders (see section "Adverse reactions").

Suicidal behavior.

Cases of 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 understood. Due to this risk, patients should be monitored for signs of depression and/or suicidal thoughts and behavior, and treatment should be adjusted if necessary. Patients (or their caregivers) should be advised to report any symptoms of depression and/or suicidal thoughts or behavior to their physician.

Unusual or 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 signs indicating significant mood and/or personality changes. If such behavior occurs, treatment adjustment or gradual discontinuation is recommended. For information on discontinuation, see the "Dosage and administration" section.

Seizure exacerbation.

As with other antiepileptic drugs, levetiracetam may rarely increase the frequency or severity of seizures. This paradoxical effect has most frequently been reported within the first month after starting levetiracetam or during dose escalation. This effect was reversible upon discontinuation or dose reduction of the drug. Patients should be advised to seek immediate medical consultation if seizure exacerbation occurs. For example, inadequate seizure control or seizure worsening has been reported in patients with epilepsy associated with mutations in the alpha subunit of voltage-gated sodium channels.

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 QT interval prolongation, in patients taking concomitant medications that affect the QT interval, and in patients with underlying cardiac conditions or electrolyte imbalances.

Children.

Available data in pediatric patients do not indicate an effect on growth or 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). It also contains liquid maltitol; therefore, this medicinal product is contraindicated in patients with rare hereditary fructose intolerance.

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 drugs, abrupt discontinuation of levetiracetam should be avoided, as this may lead to seizures, which could have serious consequences for both the woman and the unborn child. Monotherapy should be preferred whenever possible, as treatment with multiple antiepileptic drugs may be associated with a higher risk of congenital malformations compared to monotherapy, depending on the drug combination.

Pregnancy.

Extensive post-marketing data from pregnant women treated with levetiracetam (over 1800 women, including 1500 women exposed 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 monotherapy with Keppra® in utero. However, available 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 should be used.

Physiological changes during pregnancy may affect levetiracetam concentrations. Decreased plasma concentrations of levetiracetam have been observed during pregnancy, with the reduction being more pronounced in the third trimester (up to 60% of pre-pregnancy baseline concentrations). Pregnant women receiving levetiracetam therapy should be provided with appropriate clinical monitoring.

Breastfeeding.

Levetiracetam passes into human breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam treatment is necessary during breastfeeding, the benefits and risks of treatment and the importance of breastfeeding should be carefully weighed.

Effects on fertility.
No effects on fertility were observed in animal studies. The potential risk in humans is unknown due to the lack of available clinical data.

Ability to affect reaction speed when driving or operating machinery.

Levetiracetam has a minor to moderate influence on the ability to drive or operate machinery. Due to possible individual sensitivity, some patients may experience somnolence or other central nervous system-related symptoms, particularly at the beginning of treatment or during dose escalation. Therefore, such patients should exercise caution 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 can be taken after dilution in a glass of water or in a feeding bottle. A bitter taste of levetiracetam may be perceived 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. Treatment may be initiated at this dose on the first day. However, a lower initial dose of 250 mg twice daily may be prescribed by the physician based on 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 to 17 years) with body weight < 50 kg and children from 1 month of age

The physician should select the most appropriate pharmaceutical form, dosage strength, and formulation based on body weight, age, and required dose. For information on dose adjustment according to body weight, see the section «Children».

Discontinuation of treatment

If discontinuation of treatment is necessary, withdrawal of levetiracetam is recommended to be gradual (e.g., for adults and adolescents with body weight ≥ 50 kg, reduce dose by 500 mg twice daily every 2–4 weeks; for infants from 6 months of age, children, and adolescents with body weight < 50 kg, reduce dose by no more than 10 mg/kg twice daily every two weeks; for infants under 6 months of age, reduce 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.

In 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 of 50 kg or more, 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 women).
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
with renal impairment

(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, creatinine clearance (CC) in ml/min/1.73 m² can be calculated from serum creatinine (mg/dl) using the following formula (Schwartz formula):

   height (cm) × ks
CC (ml/min/1.73 m²) = ------------------------------ .
  serum creatinine (mg/dl)

In full-term infants under 1 year of age, ks = 0.45; in children up to 13 years of age and adolescent females, ks = 0.55; in adolescent males, ks = 0.7.

Table 2

Dosage adjustment recommendations for infants, children, and adolescents weighing less than 50 kg with impaired renal function

(1) For doses up to 250 mg, for doses not multiples of 250 mg when the recommended dose cannot be achieved by taking several tablets, and for patients who cannot swallow tablets, Keppra® 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 dosage form, strength, and formulation based on age, body weight, and required dose.

Keppra® oral solution is preferred for infants and children under 6 years of age. Additionally, the available tablet strengths are not suitable for initial treatment of children weighing less than 25 kg, for patients unable to swallow tablets, or for doses below 250 mg. In these cases, Keppra® oral solution should be used.

Monotherapy

The safety and efficacy of Keppra® 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 diagnosed for the first time

See section above «Adults (≥ 18 years) and adolescents (12–17 years) with body weight ≥ 50 kg».

Adjunctive therapy in infants (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 increases or decreases should not exceed 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 for all indications, see section above «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

(1) For children with body weight of 25 kg or less, treatment should be initiated with Keppra® 100 mg/ml oral solution.

(2) For children with body weight of 50 kg and above, the same doses as in adults should be used.

Adjunctive 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.

Infants should start treatment with Keppra® 100 mg/ml oral solution.

Table 4

Recommended doses for infants aged 1 to 6 months

Method of oral solution administration

Dosage should be measured using the oral dosing syringe|syringe pump| provided in the package.

Three types of packaging|capacity| are available:

• 300 ml bottle with a 10 ml oral syringe (corresponds to 1000 mg of levetiracetam) with a graduation of 0.25 ml (corresponds to 25 mg) – for children aged 4 years and older, adolescents, and adults;
• 150 ml bottle with a 3 ml oral syringe (corresponds to 300 mg|milligram-equivalents| of levetiracetam) with a graduation of 0.1 ml| (corresponds to 10 mg|milligram-equivalents|) – for infants and young children aged 6 months to < 4 years;
• 150 ml bottle with a 1 ml oral syringe (corresponds to 100 mg of levetiracetam) with a graduation of 0.05 ml (corresponds to 5 mg) – for infants aged 1 to < 6 months.

The measured dose should be diluted in a glass of water or in a feeding bottle.

Dosing the solution using the measuring syringe|syringe pump|:

• open|open| the bottle by pressing down and turning the cap counterclockwise (Fig. 1);
• detach the adapter from the syringe (Fig. 2); insert the adapter into the bottle neck (Fig. 3). Ensure it is securely attached;
• insert the syringe|syringe pump| into the open adapter (Fig. 4); turn the bottle upside down (Fig. 5);
• draw a small amount of solution into the syringe|syringe pump| by pulling the plunger down (Fig. 5A), then press the plunger to remove any air bubbles (Fig. 5B);
• fill the syringe|syringe pump| with solution by pulling the plunger to the mark corresponding to the required volume in milliliters (ml) as prescribed by the physician|physician| (Fig. 5C);
• turn the bottle upright (Fig. 6A). Remove the syringe|syringe pump| from the adapter (Fig. 6B);
• administer|administer| the contents of the syringe|syringe pump| into a glass of water or feeding bottle by pressing the plunger to the bottom of the syringe (Fig. 7);
• drink completely|entirely| the contents of the glass/feeding bottle;|glass|
• close the bottle with the plastic cap;
• rinse the syringe|syringe pump| with water (Fig. 8).

Children.

Keppra® oral solution can be prescribed to children from 1 month of age. The physician selects the optimal dosage form and strength based on age, body weight, and required dose. The drug is not recommended for use in children under 1 month of age due to lack of safety and efficacy data. It should be noted that tablet form should not be used for initial treatment in children weighing less than 25 kg when high doses are required; in patients unable to swallow tablets; or for doses below 250 mg. In such cases, the oral solution form should be used.

The safety of Keppra® as monotherapy in children and adolescents under 16 years of age has not been established.

Overdose.

Symptoms.

In cases of Keppra® overdose, somnolence, agitation, aggression, respiratory depression, decreased level of consciousness, and coma have been observed.

Treatment.

In case of acute overdose, gastric lavage or induction of emesis should be performed. There is no specific antidote for levetiracetam. Symptomatic treatment should be administered as needed, including hemodialysis (60% of levetiracetam and 74% of the main metabolite are removed).

Adverse reactions

The most commonly reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue, and dizziness. The adverse reaction profile provided is based on a pooled analysis of data from placebo-controlled clinical trials involving a total of 3416 patients who received levetiracetam. 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 the following table by system organ class, with frequencies defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), and very rare (< 1/10,000).

Table 5

* 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 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 typically occurred at the beginning of treatment (within several days to several months) and were reversible after 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. Overall, 645 patients aged 4–16 years received levetiracetam treatment in placebo-controlled and open-label add-on studies. Of these, 233 patients received levetiracetam in placebo-controlled studies. In both age groups, these data are supplemented by post-marketing safety data.

Additionally, 101 infants under 12 months of age were included 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 identified.

The overall adverse reaction profile of levetiracetam is 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 alteration (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 disturbances (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. Keppra® was not different from placebo (i.e., not inferior) in terms of change from baseline in attention and memory as measured by the Leiter-R scale and total memory score in the per-protocol population. Behavioral and emotional function results indicated worsening in patients treated with levetiracetam in terms of aggressive behavior, as assessed systematically and using validated tools (CBCL – Achenbach Child Behavior Checklist). However, in patients receiving levetiracetam in a long-term, open-label follow-up study, no average worsening of behavioral and emotional functions was observed, and aggressive behavior scores were not worse than 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 and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

After first opening of the container: 7 months.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

300 ml in a bottle; 1 bottle with a plastic measuring syringe in a cardboard box with labeling in Ukrainian.

Prescription status. Prescription only.

Manufacturer.

NextPharma SAS, France /
NextPharma SAS, France.

Manufacturer's address and location.

17 Route de Meulan, 78520 Limay, France /
17 Route de Meulan, 78520 Limay, France.

Marketing Authorization Holder.

UCB Pharma S.A., Belgium /
UCB Pharma S.A., Belgium.

Address of Marketing Authorization Holder.

Avenue de la Recherche 60, B-1070 Brussels - Belgium /
Allee de la Recherche 60, B-1070 Bruxelles - Belgium.