Deseiz®

INSTRUCTION for medical use of the medicinal product Deseyz®

Composition: levetiracetam; 1 tablet of 250 mg contains:
active substance: levetiracetam;
excipients: crospovidone (type B) (E 1202), povidone K 30, colloidal anhydrous silicon dioxide (E 551), magnesium stearate (E 470b);
film coating: hypromellose (E 464), macrogol/PEG 400 (E 1521), titanium dioxide (E 171), talc (E 553b), indigo carmine aluminum lake (E 132).

1 tablet of 500 mg contains:
active substance: levetiracetam;
excipients: crospovidone (type B) (E 1202), povidone K 30, colloidal anhydrous silicon dioxide (E 551), magnesium stearate (E 470b);
film coating: hypromellose (E 464), macrogol/PEG 400 (E 1521), titanium dioxide (E 171), talc (E 553b), iron oxide yellow (E 172).

1 tablet of 1000 mg contains:
active substance: levetiracetam;
excipients: crospovidone (type B) (E 1202), povidone K 30, colloidal anhydrous silicon dioxide (E 551), magnesium stearate (E 470b);
film coating: hypromellose (E 464), macrogol/PEG 400 (E 1521), titanium dioxide (E 171), talc (E 553b).

Medicinal form. Film-coated tablets.
Main physicochemical properties:
Tablets 250 mg: oval-shaped, film-coated tablets of blue color, with a score line on one side;
Tablets 500 mg: oval-shaped, film-coated tablets of yellow color, with a score line on one side;
Tablets 1000 mg: oval-shaped, film-coated tablets of white color, with a score line on one side.

Pharmacotherapeutic group. Antiepileptic agents. Levetiracetam.
ATC code: N03A X14.

Pharmacological properties.
Pharmacodynamics.
The active substance levetiracetam is a pyrrolidone derivative (S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine acetamide), which differs chemically 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 assumed that levetiracetam does not alter the basic characteristics of nerve cells or normal neurotransmission. In vitro studies have shown that levetiracetam affects intraneuronal Ca2+ levels by partially inhibiting the Ca2+ current through N-type calcium channels and reducing Ca2+ release from intraneuronal stores. It also partially counteracts the inhibition of GABA- and glycine-regulated currents caused by zinc and β-carbolines. Furthermore, in vitro studies have demonstrated that levetiracetam binds to specific sites in rodent brain tissues. The binding site is synaptic vesicle protein 2A, which participates in vesicle fusion and neurotransmitter release. The rank order of affinity of levetiracetam and its analogs for synaptic vesicle protein 2A correlates with their anticonvulsant potency in models of audiogenic epilepsy in mice. These results 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 wide range of models of partial and primarily generalized seizures in animals, without exhibiting proconvulsant effects. The main metabolite is inactive. In humans, the activity of the drug has been confirmed for both focal and generalized epileptic seizures (epileptiform discharges/photoparoxysmal response), indicating a broad pharmacological profile of levetiracetam.

Pharmacokinetics.
Levetiracetam is characterized by high solubility and permeability. Pharmacokinetics are linear and characterized by low inter- and intrasubject 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 drug concentration levels can be predicted from 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 (saliva/plasma concentration ratio varied from 1 to 1.7 hours after administration of oral tablets and 4 hours after oral solution).

Adults and adolescents
Absorption
Levetiracetam is rapidly absorbed after oral administration. Absolute oral bioavailability is approximately 100%. Maximum plasma concentration (Cmax) is reached within 1.3 hours after drug intake. Steady state is achieved after 2 days of twice-daily administration. Cmax is typically 31 μg/mL and 43 μg/mL after a single 1000 mg dose and repeated 1000 mg dose 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 main metabolite significantly bind 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 occurs in a wide range of tissues, including blood cells. Metabolite ucb L057 is pharmacologically inactive. Two minor metabolites have also been identified: one formed by hydroxylation of the pyrrolidone ring (1.6% of dose), and another by opening of the pyrrolidone ring (0.9% of dose). Other unidentified components accounted for only 0.6% of the dose. No interconversion of enantiomers of levetiracetam or its main metabolite was observed in vivo. In vitro studies have shown that levetiracetam and its main 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 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 indicate that significant enzyme induction in vivo is not expected. Therefore, drug interactions with other substances or vice versa are unlikely.

Elimination
The elimination half-life of the drug from plasma in adults is 7±1 hours and does not depend on dose, route of administration, or repeated use. Mean total clearance is 0.96 mL/min/kg. The majority of the drug, on average 95% of the dose, is excreted by the kidneys (approximately 93% of the dose is excreted within 48 hours). Only 0.3% of the dose is excreted in feces. Cumulative urinary excretion of levetiracetam and its main metabolite was 66% and 24% of the dose, respectively, within the first 48 hours. Renal clearance of levetiracetam and ucb L057 is 0.6 mL/min/kg and 4.2 mL/min/kg, respectively, indicating glomerular filtration of levetiracetam with subsequent tubular reabsorption, and that the main metabolite is also excreted via active tubular secretion in addition to glomerular filtration. Elimination of levetiracetam correlates with creatinine clearance.

Elderly patients
In elderly patients, elimination half-life increases by approximately 40% (10–11 hours). This is associated with 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, patients with moderate to severe renal impairment require dose adjustment of levetiracetam according to creatinine clearance (see section "Dosage and administration"). In patients with end-stage renal disease and anuria, elimination half-life is approximately 25 hours between dialysis sessions and 3.1 hours during dialysis. During a typical 4-hour dialysis session, 51% of levetiracetam is removed.

Hepatic impairment
Pharmacokinetics of levetiracetam are not altered in patients with mild to moderate hepatic impairment. In most patients with severe hepatic impairment, clearance of levetiracetam is reduced by more than 50% due to concomitant renal impairment (see section "Dosage and administration").

Pediatric population
Children aged 4 to 12 years
After administration of 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 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 concentration-time curve (AUC) increased linearly and were dose-dependent. Elimination half-life was approximately 5 hours, apparent total clearance was 1.1 mL/min/kg.

Clinical characteristics.
Indications.
Monotherapy (first-line medicinal product) for 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 for treatment of:

• Partial seizures with or without secondary generalization in adults and children aged 6 years and older with epilepsy;
• Myoclonic seizures in adults and adolescents aged 12 years and older with juvenile myoclonic epilepsy;
• Primary generalized tonic-clonic seizures in adults and adolescents aged 12 years and older with idiopathic generalized epilepsy.

Contraindications.
Hypersensitivity to levetiracetam or to other pyrrolidone derivatives, or to any excipients of the medicinal product.

Interaction with other medicinal products and other types of interactions.
Antiepileptic medicinal products
Pre-registration data from clinical trials involving adult patients indicate that levetiracetam does not affect serum concentrations of existing 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 drug in pediatric patients, as well as in adults receiving up to 60 mg/kg/day of levetiracetam. 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 steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, according to available data, clearance of levetiracetam is 20% higher in children taking enzyme-inducing anticonvulsants. Dose adjustment is not required.

Probenecid
Probenecid (500 mg four times daily)—a drug that blocks renal tubular secretion—inhibits renal clearance of the main metabolite but not 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 concentration to potentially toxic levels. Methotrexate and levetiracetam blood levels should be carefully monitored in patients receiving both drugs simultaneously.

Oral contraceptives and pharmacokinetic interactions with other medicinal products
Levetiracetam at a daily dose of 1000 mg does not alter the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone levels) were unchanged. Levetiracetam at a daily dose of 2000 mg does not alter the pharmacokinetics of digoxin and warfarin; prothrombin time values remained unchanged. Digoxin, oral contraceptives, and warfarin do not affect the pharmacokinetics of levetiracetam when used concomitantly.

Laxatives
In isolated cases, reduced effectiveness of levetiracetam has been reported when used concomitantly with the osmotic laxative macrogol taken orally with levetiracetam. Therefore, macrogol should not be taken orally within one hour before or one hour after taking levetiracetam.

Food and alcohol
The extent of absorption of levetiracetam is independent of food intake, but the rate of absorption may be slightly reduced when taken with food. There are no data on interaction between levetiracetam and alcohol.

Special precautions for use.
Renal impairment
Patients with renal impairment may require dose adjustment of levetiracetam. Patients with severe hepatic impairment should have renal function assessed before determining the drug dose (see section "Dosage and administration").

Acute kidney injury
Very rarely, acute kidney injury has been reported with the use of levetiracetam, with onset ranging from several days to several months.

Complete blood count
Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leukopenia, thrombocytopenia, and pancytopenia) have been described in association with levetiracetam use, usually at the beginning of treatment. Complete blood count is recommended in patients who experience significant weakness, fever, recurrent infections, or bleeding disorders (see section "Adverse reactions").

Abnormal and aggressive behavior
Levetiracetam may cause psychotic symptoms and behavioral disturbances, including irritability and aggression. Patients receiving levetiracetam therapy should be monitored for the development of psychiatric signs indicating significant changes in mood and/or personality. If such behavior is observed, consideration should be given to adjusting treatment or gradually discontinuing therapy. If discontinuation is considered, see section "Dosage and administration".

Increased seizure frequency
As with any antiepileptic drug, levetiracetam may lead to increased frequency and severity of seizures. This paradoxical effect has mostly been reported during the first month after starting levetiracetam or increasing the dose, and it is reversible after discontinuation of the drug or dose reduction. Patients should be advised to contact their physician immediately if seizures worsen.

Prolongation of QT interval on 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 QTc prolongation, patients receiving medicinal products that affect QTc interval, or patients with pre-existing cardiac conditions or electrolyte imbalances.

Suicidality
Cases of suicide, suicide attempts, suicidal thoughts, and suicidal behavior have been observed in patients treated with antiepileptic medicinal products (including levetiracetam). A meta-analysis of results from randomized placebo-controlled trials of antiepileptic drugs showed a slight increase in the risk of suicidal thoughts and behavior. The mechanism of this risk is not understood. Therefore, patients should be monitored for signs of depression, suicidal thoughts, and behavior, and treatment should be adjusted as necessary. Patients (and their caregivers) should be warned to report any symptoms of depression, suicidal thoughts, and behavior to their physician.

Children.
The tablet form of the medicinal product is not suitable for use in infants and children under 6 years of age. Available data in children do not indicate effects on development and sexual maturation. However, the long-term impact on learning ability, intelligence, development, endocrine functions, sexual maturation, and reproductive function in children remains unknown.

Use during pregnancy or breastfeeding.
Women of childbearing potential
Special recommendations should be provided to women of childbearing potential. Levetiracetam treatment should be reviewed if a woman plans pregnancy. As with all antiepileptic drugs, abrupt discontinuation of levetiracetam should be avoided, as this may lead to seizures, which can have serious consequences for the woman and the unborn child. Monotherapy should be preferred when possible, as treatment with multiple antiepileptic drugs may be associated with a higher risk of congenital malformations than monotherapy, depending on the combination of drugs used.

Pregnancy
A large amount of post-marketing data from pregnant women who used levetiracetam (more than 1800 women, including 1500 women who used the drug during the first trimester) do not indicate an increased risk of major congenital malformations. There is limited data on the development of the nervous system in children exposed to levetiracetam monotherapy in utero. However, available epidemiological studies (approximately 100 children) do not indicate an increased risk of disorders or delayed development of the nervous system. Levetiracetam may be used during pregnancy if, after careful assessment, it is considered clinically necessary. In such cases, the lowest effective dose is recommended. Physiological changes during pregnancy may alter levetiracetam concentrations. Decreased plasma concentrations of levetiracetam have been observed during pregnancy. This decrease is most pronounced in the third trimester (up to 60% of pre-pregnancy concentration). Adequate clinical monitoring of pregnant women receiving levetiracetam should be ensured.

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 and the importance of breastfeeding should be weighed.

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 effect on the ability to drive or operate machinery. Due to possible individual sensitivity, some patients may experience drowsiness and other symptoms related to central nervous system effects, especially at the beginning of treatment or during dose escalation. Therefore, such patients should be cautious when engaging in activities requiring increased attention, such as driving a car or operating machinery. Patients are advised to refrain from driving vehicles and operating machinery until it is established that their ability to perform such activities is not impaired.

Dosage and administration.
Tablets should be taken orally, swallowed with sufficient liquid, regardless of food intake. When taken orally, levetiracetam may have a bitter taste. The daily dose should be divided into two equal doses.

Monotherapy
Adults and adolescents aged 16 years and older
Monotherapy in adults and children aged 16 years and older should be initiated with the recommended dose of 500 mg per day (250 mg twice daily), with subsequent increase of the initial therapeutic dose to 1000 mg per day (500 mg twice daily) after 2 weeks. The dose may be increased by 500 mg per day (250 mg twice daily) every 2 weeks, depending on clinical effect. The maximum daily dose is 3000 mg per day (1500 mg twice daily).

Children and adolescents under 16 years of age
Safety and efficacy of levetiracetam as monotherapy in children and adolescents under 16 years of age have not been established. Data are lacking.

Adjunctive therapy
Adjunctive therapy for adults (aged 18 years and older) and adolescents (aged 12 to 17 years) with body weight ≥ 50 kg
Initial therapeutic dose is 1000 mg per day (500 mg twice daily). This is the initial dose administered on the first day of treatment. Depending on clinical picture and drug tolerability, the daily dose may be increased up to a maximum of 3000 mg per day (1500 mg twice daily). Dose adjustments of 1000 mg per day (500 mg twice daily) may be made every 2–4 weeks.

Adjunctive therapy for children aged 6 years and adolescents (aged 12 to 17 years) with body weight < 50 kg
Infants and children under 6 years of age should preferably be given levetiracetam in the form of oral solution. Oral solution of levetiracetam should be used in children aged 6 years for dosing below 250 mg, for doses not multiples of 250 mg when the recommended dosage cannot be achieved by taking several tablets, and for patients who cannot swallow tablets. The lowest effective dose should be used. Initial dose for a child or adolescent with body weight of 25 kg should be 250 mg twice daily, maximum dose – 750 mg twice daily. For children with body weight over 50 kg, dosing should follow the adult regimen.

Adjunctive therapy for infants aged 1 to 6 months
Infants should be given the medicinal product in the form of oral solution.

Discontinuation of treatment
If discontinuation of the medicinal product is necessary, gradual withdrawal is recommended (e.g., for adults and adolescents with body weight ≥ 50 kg – reduce dose by 500 mg twice daily every 2–4 weeks; for children and adolescents with body weight < 50 kg – reduce single dose by no more than 10 mg/kg twice daily every 2 weeks).

Special patient groups
Elderly patients (aged 65 years and older)
Dose adjustment is recommended for elderly patients with impaired renal function (see below "Renal impairment").

Renal impairment
Daily dose should be individually adjusted according to renal function. For dose adjustment in adults, use the table below (Table 1). To adjust dose using the table, creatinine clearance (CCr) in mL/min must be determined. CCr for adults and adolescents with body weight > 50 kg can be calculated based on serum creatinine concentration (mg/dL) using the formula:

Then the CC is adjusted according to body surface area (BSA) as shown below:

Table 1 Dosing regimen in renal impairment for adults and adolescents with renal impairment and body weight over 50 kg

* On the first day of treatment with levetiracetam, a loading dose of 750 mg is recommended. ** An additional dose of 250−500 mg is recommended after dialysis. For children with renal impairment, the dose of levetiracetam should be adjusted according to renal function, as the clearance of levetiracetam is related to renal function. This recommendation is based on a study conducted in adult patients with impaired renal function. For adolescents, children, and infants, the CC in ml/min/1.73 m2 can be calculated based on serum creatinine concentration (mg/dl) using the following formula (Schwartz formula):

In children under 13 years of age and adolescent girls, ks = 0.55; in adolescent boys, ks = 0.7. Table 2 Recommendations for dose adjustment in children under 6 years of age and adolescents with impaired renal function and body weight less than 50 kg

(1) For doses up to 250 mg, for doses not multiples of 250 mg when the recommended dosage cannot be achieved by taking several tablets, and for patients unable to swallow tablets, oral solution of levetiracetam should be used. (2) On the first day of treatment, a loading dose of levetiracetam 15 mg/kg (0.15 mL/kg) is recommended. (3) After dialysis, an additional dose of 5–10 mg/kg (0.05–0.10 mL/kg) is recommended. Hepatic impairment Dose adjustment is not required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, creatinine clearance may not fully reflect the degree of renal impairment. Therefore, for patients with creatinine clearance < 60 mL/min/1.73 m², the daily maintenance dose should be reduced by 50%. Children The physician should prescribe the most appropriate pharmaceutical form, dosage strength, and formulation based on age, body weight, and calculated dose. The tablet formulation is not recommended for children under 6 years of age. This patient group should preferably be treated with levetiracetam oral solution. Furthermore, the available tablet strengths are not suitable for initial treatment of children weighing less than 25 kg, for patients unable to swallow tablets, or for administration of doses below 250 mg. In all the above-mentioned cases, treatment should be initiated with levetiracetam oral solution. Children. The tablet formulation is not recommended for children under 6 years of age. Infants from 1 month of age and children under 6 years of age should be treated with levetiracetam oral solution. Overdose. Symptoms In cases of levetiracetam overdose, somnolence, agitation, aggression, respiratory depression, depressed 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. 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 profile of reported adverse reactions 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 experience from appropriate extended open-label studies and 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. 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 3 by system organ class and frequency of occurrence. Frequency is defined as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000). Table 3

* Prevalence is significantly higher in Japanese patients compared to non-Japanese patients. Description of individual 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 were usually observed at the beginning of treatment (within several days to several months) and were reversible upon discontinuation of treatment. Children Among patients aged 1 month to 4 years, a total of 190 patients received levetiracetam treatment during placebo-controlled and open-label add-on studies. Of these patients, 60 received levetiracetam treatment during placebo-controlled studies. Among patients aged 4–16 years, a total of 645 patients received levetiracetam treatment during placebo-controlled and open-label add-on studies. Of these patients, 233 received levetiracetam treatment during placebo-controlled studies. Safety data from both age groups were supplemented with post-marketing experience. Additionally, 101 infants under 12 months of age were included in a post-marketing safety study. No new safety data were obtained for levetiracetam use in infants under 12 months of age with epilepsy. The adverse reaction profile of levetiracetam is generally similar across different age groups and all approved epilepsy indications. Safety results in children from placebo-controlled clinical trials 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%) occurred more frequently than in other age groups or in the overall safety profile. In infants and children aged 1 month to 4 years, irritability (very common: 11.7%) and coordination disorders (common: 3.3%) occurred more frequently than in other age groups or in the overall safety profile. In a double-blind, placebo-controlled safety study in children conducted to demonstrate non-inferiority of the drug compared to active control, the effects of levetiracetam on cognitive and neuropsychological parameters were evaluated in children aged 4 to 16 years with partial seizures. Levetiracetam did not differ from placebo (was not inferior) in terms of change from baseline in attention and memory as measured by the Leiter-R scale and total memory test score in the per-protocol population. Results related to behavioral and emotional functions indicated an increase in aggressive behavior in patients treated with levetiracetam, as assessed systematically and standardized using validated instruments (CBCL – Achenbach Child Behavior Checklist). However, in patients receiving levetiracetam during a long-term open-label follow-up study, no mean 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 drug authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system. Shelf life. 3 years. Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children. Packaging. 10 tablets in a blister; 3 blisters in a carton. Prescription status. Prescription only. Marketing authorization holder. JSC "Pharmaceutical Company "Darnitsya". Address of the marketing authorization holder and location of its business operations. 13 Borispilska Street, Kyiv, 02093, Ukraine. Manufacturer.

1. Rontis Hellas Medical and Pharmaceutical Products S.A.
2. PHARMOS MT Limited.

Location of manufacturer and address of its business operations.

1. Larissa Industrial Area, P.O. Box 3012, Larissa, 41 500, Greece.
2. XF62EX, Casem Industriali Hal Far, Hal Far, Birzebbuga, BBG 3000, Malta.