Lacozam®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LACOSAM® (LACOSAM)

Composition:

Active substance: lacosamide;

1 tablet contains 200 mg of lacosamide;

Excipients: microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, hydroxypropyl cellulose, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating: polyvinyl alcohol (E 1203), titanium dioxide (E 171), macrogol 3350 (E 1521), talc (E 553 b), FD&C Blue #2/aluminum lake of indigo carmine (E 132).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

Blue, elongated, biconvex, film-coated tablets, with "200" embossed on one side and smooth on the other.

Pharmacotherapeutic group. Antiepileptic drugs. Other antiepileptic drugs.

ATC code N03A X18.

Pharmacological Properties

Mechanism of Action

The active substance, lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide), is a functionalized amino acid.

The precise mechanism of the antiepileptic action of lacosamide has not been fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances the slow inactivation of voltage-gated sodium channels, thereby promoting stabilization of hyperexcitable neuronal membranes.

Pharmacodynamics

The anticonvulsant efficacy of lacosamide has been demonstrated in various animal models of partial and primarily generalized seizures, as well as in delaying kindling (epileptogenic effect in experimental animals). In preclinical studies, lacosamide demonstrated synergistic or additive anticonvulsant effects when used in combination with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, topiramate, or gabapentin.

Clinical Efficacy and Safety

The efficacy of lacosamide as adjunctive therapy at the recommended doses (200 mg/day, 400 mg/day) was established in three multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. The efficacy of 600 mg lacosamide daily was also demonstrated in controlled adjunctive therapy trials; however, the efficacy of this dose was comparable to that of 400 mg/day, and the lower dose was better tolerated. Adverse reactions involving the central nervous system and gastrointestinal tract were more frequent with the 600 mg/day dose. Therefore, the 600 mg/day dose is not recommended. The maximum recommended dose is 400 mg/day. These trials included 1308 patients with partial seizures with or without secondary generalization and a mean history of epilepsy of 23 years. The primary objective was to evaluate the efficacy and safety of lacosamide when used concomitantly with 1–3 other antiepileptic drugs in patients with uncontrolled partial seizures. Overall, the proportion of patients achieving a 50% reduction in seizure frequency was 23%, 34%, and 40% in the placebo, 200 mg/day, and 400 mg/day lacosamide groups, respectively.

The pharmacokinetics and safety of a single intravenous loading dose of lacosamide were evaluated in a multicenter, open-label study designed to assess the safety and tolerability of rapid initiation of lacosamide treatment using a single intravenous loading dose (specifically 200 mg), followed by twice-daily oral administration (equivalent to the intravenous dose) as adjunctive therapy in adult patients aged 16 to 60 years with partial seizures.

Pharmacokinetics

Absorption

Lacosamide is rapidly and completely absorbed after oral administration. The bioavailability of lacosamide tablets is approximately 100%. After oral intake, plasma concentrations of unchanged lacosamide rise quickly, with Cmax reached within 0.5–4 hours. The film-coated tablet and oral syrup formulations of lacosamide are bioequivalent. Food does not affect the rate or extent of absorption.

Distribution

The volume of distribution is approximately 0.6 L/kg. Plasma protein binding is less than 15%.

Biotransformation

Approximately 95% of the dose is excreted in the urine as lacosamide and its metabolites. The metabolism of lacosamide has not been fully characterized.

The main compounds excreted in urine are unchanged lacosamide (approximately 40% of the dose) and its O-desmethyl metabolite (less than 30%).

The fraction of polar compounds in urine (likely serine derivatives) accounts for approximately 20%, but these are detected only in small amounts (0–2%) in the plasma of some patients. Small quantities of other metabolites found in urine range from 0.5% to 2%.

In vitro data indicate that CYP2C9, CYP2C19, and CYP3A4 are capable of catalyzing the formation of the O-desmethyl metabolite; however, the primary isoenzyme involved has not been confirmed in vivo. No clinically relevant differences in lacosamide exposure were observed when comparing pharmacokinetics between extensive metabolizers (individuals with functional CYP2C19) and poor metabolizers (individuals with deficient functional CYP2C19). Additionally, a drug interaction study with omeprazole (a CYP2C19 inhibitor) demonstrated no clinically significant changes in lacosamide plasma concentrations, indicating minimal relevance of this metabolic pathway.

The plasma concentration of the O-desmethyl metabolite is approximately 15% of the lacosamide concentration. This major metabolite has no known pharmacological activity.

Elimination

Lacosamide is primarily eliminated from systemic circulation via renal excretion and biotransformation. After oral and intravenous administration of radiolabeled lacosamide, approximately 95% of radioactivity was recovered in urine and less than 0.5% in feces. The elimination half-life of unchanged lacosamide is approximately 13 hours. Pharmacokinetics are dose-proportional, time-independent, and characterized by low inter- and intra-subject variability. Steady-state plasma concentrations are achieved within 3 days with twice-daily dosing. Accumulation results in approximately a two-fold increase in plasma concentration.

A single 200 mg loading dose achieves a plasma lacosamide concentration close to the steady-state level observed with 100 mg administered orally twice daily.

Pharmacokinetics in Special Patient Populations

Sex. Clinical studies have shown that sex has no clinically relevant effect on lacosamide plasma concentrations.

Renal Impairment. AUC values of lacosamide increased by approximately 30% in patients with mild to moderate renal impairment, and by 60% in patients with severe renal impairment and those with end-stage renal disease requiring hemodialysis. However, these conditions do not affect Cmax.

Lacosamide is effectively removed from plasma during hemodialysis. After 4 hours of hemodialysis, the AUC of lacosamide is reduced by approximately 50%. Therefore, a dose adjustment is recommended following hemodialysis (see section "Dosage and Administration"). The exposure to the O-desmethyl metabolite increases several-fold in patients with moderate and severe renal impairment. In patients with end-stage renal disease not undergoing hemodialysis, these values were elevated and continuously increased over 24 hours, as shown by serial analyses. It is unknown whether increased exposure to the lacosamide metabolite in patients with end-stage renal disease may lead to adverse reactions; however, no pharmacological activity has been identified for this metabolite.

Hepatic Impairment. Increased lacosamide concentrations (approximately 50% higher AUCnorm) were observed in patients with moderate hepatic impairment (Child-Pugh class B). The increased exposure to lacosamide was partly attributed to reduced renal function in the study population. Reduced non-renal clearance in these patients resulted in a 20% increase in lacosamide AUC. The pharmacokinetics of lacosamide in patients with severe hepatic impairment have not been studied (see section "Dosage and Administration").

Elderly Patients (aged 65 years and older). In studies involving elderly men and women, including four patients aged 75 years or older, AUC values were approximately 30% and 50% higher, respectively, compared to younger patients, partly due to lower body weight. When adjusted for body weight, this difference was 26% and 23%, respectively. Increased variability in lacosamide exposure was also observed in elderly patients. The studies indicated only a slight reduction in renal clearance of lacosamide in elderly patients.

The total dose of the medicinal product should not be reduced unless indicated due to impaired renal function (see section "Dosage and Administration").

Clinical Characteristics

Indications.
Use as adjunctive therapy in the treatment of partial-onset seizures, with or without secondary generalization, in patients aged 16 years and older with epilepsy.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Atrioventricular block of second or third degree in medical history.

Interaction with other medicinal products and other forms of interaction

Lacosamide should be used with caution in patients receiving medicinal products that may cause PR interval prolongation (particularly antiepileptic drugs that are sodium channel blockers) and in patients receiving Class I antiarrhythmic agents. However, subgroup analyses from clinical trials did not show additional PR interval prolongation in patients receiving lacosamide concomitantly with carbamazepine or lamotrigine.

In vitro data

Overall study results indicate a low likelihood of lacosamide interactions with other medicinal products. In vitro studies show that lacosamide does not induce CYP1A2, 2B6, or 2C9 enzymes and does not inhibit CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, or 2E1 at plasma concentrations observed in clinical trials. In vitro studies indicate that lacosamide is not transported by P-glycoprotein in the intestine. In vitro data suggest that CYP2C9, CYP2C19, and CYP3A4 are capable of catalyzing the formation of the O-desmethyl metabolite.

In vivo data

In vivo, lacosamide does not clinically significantly inhibit or induce CYP2C19 and 3A4 enzymes.

Lacosamide did not affect the AUC of midazolam (metabolized via CYP3A4; lacosamide administered at 200 mg twice daily), although the Cmax of midazolam was slightly increased (by 30%). Lacosamide did not affect the pharmacokinetics of omeprazole (metabolized via CYP2C19 and 3A4; lacosamide administered at 300 mg twice daily).

The CYP2C19 inhibitor omeprazole (40 mg once daily) did not cause clinically significant changes in lacosamide exposure. Therefore, it is unlikely that moderate CYP2C19 inhibitors will have a clinically significant effect on systemic lacosamide exposure.

Concomitant use of strong CYP2C9 inhibitors (e.g., fluconazole) and strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, ritonavir, clarithromycin) is recommended with caution, as increased systemic exposure to lacosamide is possible. Such interactions have not been established in vivo, but their potential is based on in vitro data.

Strong enzyme inducers such as rifampicin or St John’s wort (Hypericum perforatum) may cause a moderate decrease in systemic lacosamide exposure. Therefore, caution is advised when initiating or discontinuing treatment with such agents.

Antiepileptic drugs

Lacosamide did not cause significant changes in plasma concentrations of carbamazepine or valproic acid. In turn, carbamazepine and valproic acid did not affect plasma levels of lacosamide. According to population pharmacokinetic analysis, concomitant therapy with other enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, phenobarbital at various doses) reduced total systemic exposure to lacosamide by 25% in adult patients.

Oral contraceptives

An interaction study showed no evidence of clinically significant interaction between lacosamide and the oral contraceptives ethinylestradiol and levonorgestrel. Progesterone concentrations were not altered with concomitant administration of these drugs.

Others

Lacosamide did not affect the pharmacokinetics of digoxin. No clinically significant interaction between lacosamide and metformin was observed.

Concomitant administration of warfarin with lacosamide did not reveal clinically significant changes in the pharmacokinetics or pharmacodynamics of warfarin.

Although pharmacokinetic data on the interaction between lacosamide and alcohol are lacking, a pharmacodynamic effect cannot be excluded.

The extent of lacosamide protein binding is low, less than 15%. Therefore, clinically significant interactions with other medicinal products that bind to plasma proteins are unlikely.

Special precautions for use

Dizziness

Treatment with lacosamide is associated with dizziness, which may increase the frequency of accidental injuries and falls. Therefore, patients should be warned about the potential effect of the medicinal product, advised to exercise caution, and encouraged to become familiar with the potential adverse effects of the medicinal product in the section "Adverse reactions".

Cardiac rhythm and conduction

In clinical trials, dose-dependent prolongation of the PR interval was observed during lacosamide administration. The medicinal product should be used with caution in patients with known proarrhythmic conditions such as cardiac conduction disorders or serious cardiac diseases (e.g., ischemia/myocardial infarction, heart failure, structural heart disease, or cardiac sodium channelopathies), in patients taking medicinal products that affect cardiac conduction—particularly antiarrhythmic agents and antiepileptic sodium channel blockers (see section "Interaction with other medicinal products and other forms of interaction"), and in elderly patients.

In these patients, ECG monitoring should be considered before increasing the lacosamide dose above 400 mg/day and after titration of lacosamide to steady state.

In placebo-controlled clinical trials of lacosamide in patients with epilepsy, no cases of atrial fibrillation or flutter were reported; however, such events were reported during open-label epilepsy trials and in post-marketing surveillance.

During post-marketing surveillance of adverse events, cases of second-degree or higher atrioventricular block have been reported. Ventricular tachyarrhythmias have been observed in patients with proarrhythmic conditions. Rarely, these cases led to asystole, cardiac arrest, or fatal outcomes in patients with pre-existing proarrhythmic conditions.

Patients should be informed about the symptoms of cardiac arrhythmia (e.g., slow, fast, or irregular pulse, palpitations, shortness of breath, confusion, or loss of consciousness). Patients should seek immediate medical attention if any of these symptoms occur.

Suicidal ideation and behaviour

Suicidal thoughts and behaviour have been observed in patients receiving antiepileptic medicinal products for various conditions. A meta-analysis of randomized, placebo-controlled clinical trials of antiepileptic medicinal products also demonstrated a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is unknown, and available data do not exclude the possibility of increased risk with lacosamide use.

Therefore, patients should be monitored for signs of suicidal thoughts and behaviour, and appropriate treatment should be initiated if necessary. Patients (and caregivers) should be advised to seek medical advice immediately if such signs occur (see section "Adverse reactions").

Potential for electroclinical worsening in specific pediatric epilepsy syndromes

The safety and efficacy of lacosamide in pediatric patients with epilepsy syndromes involving both partial and generalized seizures have not been established.

Use during pregnancy or breastfeeding

Women of childbearing potential

Physicians should discuss family planning and contraceptive methods with women of childbearing potential who are taking lacosamide (see "Pregnancy" below).

If a woman plans to become pregnant, the continued use of lacosamide should be re-evaluated.

Pregnancy

Risk associated with epilepsy and use of antiepileptic drugs in general: The incidence of congenital malformations in newborns whose mothers received treatment for epilepsy is 2–3 times higher than in the general population (approximately 3%). Polytherapy in pregnant women has been associated with an increased incidence of congenital malformations in children, although it remains unclear to what extent this is related to treatment versus the underlying disease. In addition, effective antiepileptic therapy should not be discontinued during pregnancy, as worsening of the disease may have serious consequences for both mother and fetus.

Risk associated with lacosamide use: There are no adequate data on the use of lacosamide in pregnant women. Animal studies (in rats and rabbits) did not reveal teratogenic effects of the drug, but embryotoxicity was observed when the drug was administered at maternally toxic doses. Whether there is a risk in humans is unknown. Lacosamide should not be used during pregnancy except when clearly needed (i.e., when the benefit to the pregnant woman clearly outweighs the potential risk to the fetus). If a woman is planning pregnancy, the need for this medicinal product should be carefully considered.

Breastfeeding

Lacosamide is excreted in human breast milk. The risk to newborns/infants cannot be excluded. Breastfeeding is recommended to be discontinued during treatment with lacosamide.

Fertility

No adverse effects on fertility or reproductive function in male or female rats were observed at doses where plasma drug exposure (AUC) was approximately twice that of human plasma exposure at the maximum recommended dose.

Ability to affect reaction speed when driving or operating machinery

Lacosamide has a minor or moderate influence on the ability to drive a car or operate complex machinery. Treatment with this medicinal product has been associated with dizziness or blurred vision. Therefore, patients should not drive or operate potentially hazardous machinery until individual response to lacosamide is known.

Method of Administration and Dosage

The medicinal product Lacosamide® should be administered twice daily (usually once in the morning and once in the evening). If a dose is missed, the patient should take the missed dose immediately, and then continue with the next dose according to the prescribed schedule. However, if less than 6 hours remain before the next scheduled dose, the patient should wait and take the next dose of lacosamide according to the regular schedule. A double dose should not be taken.

The recommended initial dose is 50 mg twice daily (use the medicinal product in the appropriate dosage strength). After 1 week, the dose should be increased to the initial therapeutic dose of 100 mg twice daily (use the medicinal product in the appropriate dosage strength).

Depending on the therapeutic response and tolerability, the maintenance dose may be further increased by 50 mg twice daily (100 mg per day — use the medicinal product in the appropriate dosage strength) at weekly intervals, up to the maximum recommended daily dose of 400 mg (200 mg twice daily).

Initiation of lacosamide treatment with a loading dose

Treatment with the medicinal product may also be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by a maintenance dose of 100 mg twice daily (200 mg/day — use the medicinal product in the appropriate dosage strength). Further dose adjustments should be made according to individual response and tolerability, as described above. A loading dose may be prescribed to patients when the physician considers rapid achievement of stable plasma concentrations of lacosamide and therapeutic effect to be justified. The medicinal product should be administered under medical supervision due to the potential for increased frequency of serious cardiac arrhythmias and central nervous system (CNS) adverse reactions (see section "Adverse Reactions"). Administration of a loading dose has not been studied in acute conditions such as status epilepticus.

Discontinuation of treatment

According to current clinical practice, discontinuation of the medicinal product Lacosamide® is recommended to be gradual (reducing the dose by 200 mg per week).

In patients who develop a serious cardiac arrhythmia, a clinical benefit/risk assessment should be performed and lacosamide discontinued if necessary.

Special populations

Patients of elderly age (65 years and older)

Dose reduction is not required in elderly patients. Experience with the use of lacosamide in elderly patients with epilepsy is limited. The possibility of age-related reduction in renal clearance and increased AUC levels in elderly patients should be considered (see subsection "Patients with renal impairment" below and section "Pharmacokinetics").

Patients with renal impairment

No dose adjustment is required in patients with mild or moderate renal impairment (creatinine clearance > 30 mL/min).

A loading dose (200 mg) may be used in patients with mild or moderate renal impairment, but subsequent dose titration (> 200 mg/day) should be performed cautiously. For patients with severe renal impairment (creatinine clearance ≤ 30 mL/min) and those with end-stage renal disease, a maximum dose of 250 mg/day is recommended (use the medicinal product in the appropriate dosage strength). Dose titration in such patients should be performed cautiously. If a loading dose is prescribed, a single initial dose of 100 mg should be administered, followed by 50 mg twice daily during the first week (use the medicinal product in the appropriate dosage strength).

In patients undergoing hemodialysis, an additional 50% of the daily dose is recommended to be administered at the end of the dialysis session. Treatment of patients with end-stage renal disease should be performed cautiously due to limited clinical experience and the potential accumulation of a metabolite with no known pharmacological activity.

Patients with hepatic impairment

In patients with mild or moderate hepatic impairment, a maximum dose of 300 mg/day is recommended (use the medicinal product in the appropriate dosage strength).

Dose titration in these patients should be performed cautiously, considering the possibility of concomitant renal impairment. A loading dose (200 mg) may be used, but subsequent dose titration (> 200 mg/day) should be performed cautiously. The pharmacokinetics of lacosamide have not been studied in patients with severe hepatic impairment. Lacosamide should be prescribed to patients with severe hepatic impairment only if the expected therapeutic benefit outweighs the potential risks. Dose adjustment may be required based on careful monitoring of disease activity and potential adverse effects in the patient.

Paediatric patients

The medicinal product is not recommended for children under 16 years of age, as the safety and efficacy of lacosamide have not been established in these age groups.

Method of administration

Lacosamide® tablets, film-coated, are intended for oral administration. Lacosamide® may be taken with or without food.

Children.

The medicinal product is not recommended for children under 16 years of age, as the safety and efficacy of lacosamide have not been studied in these age groups.

Overdose.

Symptoms

Symptoms observed following accidental or intentional overdose of lacosamide are primarily related to the central nervous system (CNS) and gastrointestinal tract.

• No clinically significant differences in the type of adverse reactions observed in patients receiving doses above 400 mg up to 800 mg compared to those receiving therapeutic doses of lacosamide were noted.
• Reactions reported after ingestion of more than 800 mg: dizziness, nausea, vomiting, seizures (generalized tonic-clonic seizures, status epilepticus). Also observed were disturbances in cardiac conduction, shock, and coma. Fatal outcomes have been reported in patients following acute single-dose overdose (ingestion of several grams of lacosamide).

Treatment

There is no specific antidote for lacosamide overdose. Management of overdose includes general supportive measures and, if necessary, hemodialysis (see section "Pharmacological properties").

Adverse Reactions

Based on pooled results from placebo-controlled clinical trials of lacosamide as adjunctive therapy involving 1308 patients with partial-onset seizures, 61.9% of patients randomized to lacosamide and 35.2% of patients randomized to placebo experienced at least one adverse reaction. The most commonly reported adverse reactions (≥ 10%) with lacosamide use were dizziness, headache, nausea, and diplopia. These were generally mild or moderate in severity. Some of these reactions were dose-dependent, and dose reduction often led to their alleviation. The frequency and severity of central nervous system (CNS) and gastrointestinal adverse reactions generally decreased over time.

In clinical studies, treatment was discontinued due to adverse effects in 12.2% of patients in the lacosamide group compared to 1.6% in the placebo group. Dizziness was the most frequent reason for discontinuation of lacosamide therapy.

The frequency of CNS-related adverse reactions (such as dizziness) may increase after administration of a loading dose.

The following adverse reactions were identified during clinical trials and post-marketing surveillance. Adverse reaction frequencies are categorized as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), and frequency not known (cannot be estimated from available data). Within each category, reactions are listed in descending order of severity.

Blood and lymphatic system disorders:
Frequency not known — agranulocytosis¹.

Immune system disorders:
Uncommon — drug hypersensitivity¹; frequency not known — drug reaction with eosinophilia and systemic symptoms (DRESS)¹,².

Nervous system disorders:
Very common — dizziness, headache;
Common — myoclonic seizures³, ataxia, balance disorder, memory impairment, cognitive disorder, somnolence, tremor, nystagmus, hypoesthesia, dysarthria, attention disturbance, paresthesia;
Uncommon — loss of consciousness², coordination disorder, dyskinesia;
Frequency not known — seizures.

Psychiatric disorders:
Common — depression, confusional state, insomnia¹;
Uncommon — aggression, agitation¹, euphoric mood¹, psychotic disorder¹, suicide attempt¹, suicidal ideation, hallucinations¹.

Eye disorders:
Very common — diplopia;
Common — blurred vision.

Ear and labyrinth disorders:
Common — vertigo, tinnitus.

Cardiac disorders:
Uncommon — atrioventricular block¹,², bradycardia¹,², atrial fibrillation¹,², atrial flutter¹,²;
Frequency not known — ventricular tachyarrhythmia¹.

Gastrointestinal disorders:
Very common — nausea;
Common — vomiting, constipation, flatulence, dyspepsia, dry mouth, diarrhea.

Hepatobiliary disorders:
Uncommon — liver function test abnormalities², elevated liver enzymes (> 2 × ULN [upper limit of normal])¹.

Skin and subcutaneous tissue disorders:
Common — pruritus, rash¹;
Uncommon — angioneurotic edema¹, urticaria¹;
Frequency not known — Stevens-Johnson syndrome¹, toxic epidermal necrolysis¹.

Musculoskeletal and connective tissue disorders:
Common — muscle spasm.

General disorders:
Common — gait disturbance, asthenia, fatigue, irritability, feeling drunk.

Injury, poisoning and procedural complications:
Common — falls, skin fissures, contusion.

¹ Adverse reactions reported during the post-marketing period.
² See section "Selected adverse reactions" below.
³ Reported in trials of primary generalized tonic-clonic seizures.

Selected Adverse Reactions

Lacosamide use is associated with dose-dependent prolongation of the PR interval. Adverse reactions related to PR interval prolongation (e.g., atrioventricular block, loss of consciousness, bradycardia) may occur.

In additional clinical trials of patients with epilepsy, first-degree atrioventricular block was observed uncommonly — in 0.7% and 0.5% of patients receiving lacosamide at doses of 200 mg and 600 mg, respectively, and was not observed at 400 mg or in the placebo group. Second- or higher-degree atrioventricular block was not observed in patients receiving lacosamide during clinical trials. However, cases of second- and third-degree atrioventricular block associated with lacosamide treatment have been reported during post-marketing surveillance.

Loss of consciousness occurred uncommonly in clinical trials, with no difference in frequency between patients with epilepsy (n = 944) receiving lacosamide (0.1%) and those receiving placebo (0.3%, n = 364).

Atrial fibrillation or flutter were not reported during short-term clinical trials; however, both events were observed in open-label epilepsy trials and during post-marketing monitoring.

Laboratory test abnormalities.
Abnormalities in liver function parameters were observed during placebo-controlled trials of lacosamide in adult patients with partial-onset seizures who were concurrently taking 1 to 3 antiepileptic drugs. ALT (alanine aminotransferase) levels increased to ≥ 3 × ULN (upper limit of normal) in 0.7% (7/935) of patients receiving lacosamide and in 0% (0/356) of placebo-treated patients.

Multiorgan hypersensitivity reactions.
Multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms, DRESS) have been reported in patients taking certain antiepileptic drugs. These reactions vary in presentation but typically involve fever, rash, and multiorgan involvement. If multiorgan hypersensitivity is suspected, lacosamide should be discontinued.

Pediatric Population

The safety profile of lacosamide in placebo-controlled (255 patients aged 1 month to 4 years and 343 patients aged 4 to 17 years) and open-label clinical trials (847 patients aged 1 month to 18 years) as adjunctive therapy in pediatric patients with partial-onset seizures was consistent with the safety profile observed in adults. Because data on use in children are limited, lacosamide is not recommended for use in patients under 16 years of age.

Additional adverse reactions observed in pediatric patients included pyrexia, nasopharyngitis, pharyngitis, decreased appetite, abnormal behavior, and lethargy. Somnolence was reported more frequently in pediatric patients (≥ 1/10) compared to adults (≥ 1/100 to < 1/10).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life: 4 years.

Storage conditions
Store in the original packaging, out of reach of children. No special storage conditions required.

Packaging
14 tablets per blister; 2 or 4 blisters per cardboard pack.

Prescription status
Prescription only.

Manufacturer:
DzenePharm S.A.

Manufacturer's address:
18th km Marathonos Avenue, Pallini, 153 51, Greece.

Marketing Authorization Holder:
LLC "ASINO UKRAINE"

Address of Marketing Authorization Holder:
8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

In case of adverse effects or questions regarding the safety of this medicinal product, please contact the pharmacovigilance department of LLC "ASINO UKRAINE" at: 8 Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +38 044 281 2333.