Novolera^® EPI (Tablets, Solution) Instructions for Use

ATC Code

N03AX18 (Lacosamide)

Active Substance

Lacosamide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiepileptic drug

Pharmacotherapeutic Group

Antiepileptic drugs; other antiepileptic drugs

Pharmacological Action

Mechanism of action

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

The exact mechanism of the antiepileptic action of lacosamide has not been established. In in vitro electrophysiological studies, Lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, leading to stabilization of hyperexcitable neuronal membranes.

Pharmacodynamic effects

Lacosamide prevented the development of seizures in a large number of animal models of partial and primary generalized epilepsy, and also delayed the development of increased seizure readiness. In preclinical studies, Lacosamide in combination with levetiracetam, carbamazepine, phenytoin, valproates, lamotrigine, topiramate, or gabapentin demonstrated synergistic or additive anticonvulsant effects.

Clinical efficacy and safety

Partial seizures

Monotherapy

The efficacy of lacosamide as monotherapy was demonstrated in a double-blind efficacy study compared with carbamazepine (controlled release), conducted in parallel groups involving 886 patients aged 16 years or older with newly or previously diagnosed epilepsy. The study included patients with unprovoked partial seizures with or without secondary generalization. Patients were randomized into 2 groups in a 1:1 ratio, receiving carbamazepine and Lacosamide (in the “tablets” dosage form), respectively. Doses were titrated based on response to therapy and ranged from 400-1200 mg/day for carbamazepine and 200-600 mg for lacosamide. The duration of therapy was up to 121 weeks, depending on the response.

The expected 6-month seizure-free period was achieved in 89.8% of patients receiving lacosamide therapy and 91.1% in the carbamazepine group (using the Kaplan-Meier survival analysis method). The adjusted absolute difference between the groups was 1.3% (95% confidence interval [CI]: -5.5; 2.8). The expected 12-month seizure-free period by the Kaplan-Meier method was 77.8% for lacosamide therapy and 82.7% for carbamazepine (controlled release) therapy.

In elderly patients (over 65 years, 62 patients in the lacosamide group, 57 in the carbamazepine group), the proportion achieving a 6-month seizure-free period was the same in both groups. It was also comparable to that observed in the rest of the population. Among elderly patients, 55 (88.7%) received a maintenance dose of 200 mg/day Lacosamide, 6 (9.7%) received 400 mg/day, and the dose exceeded 400 mg/day in 1 patient (1.6%).

Conversion to monotherapy

The efficacy and safety of lacosamide during conversion to monotherapy were studied in a multicenter, double-blind, randomized, historically controlled trial. In this study, 425 patients aged 16 to 70 years with partial seizures taking stable doses of one or two antiepileptic drugs were randomized 3:1 to two groups for conversion to lacosamide monotherapy, receiving 400 mg or 300 mg of lacosamide per day, respectively. The starting dose was 200 mg/day (100 mg twice daily). The maintenance dose was taken for at least 3 days before the start of the conversion to monotherapy. The percentage of patients who met predefined study exit criteria was compared with historical control data. The historical control was represented by the results of a pooled analysis of control groups from 8 studies with a similar design that used a subtherapeutic dose of an antiepileptic drug. Statistical superiority of lacosamide at a dose of 400 mg/day over historical control was demonstrated, indicating achievement of the primary efficacy endpoint. Furthermore, Lacosamide at a dose of 300 mg/day was shown to be superior to historical control. Among patients who completed titration and began withdrawal of antiepileptic drugs (284 and 99, respectively), monotherapy was maintained by 71.5% and 70.7% of patients, respectively, for an average of 71 days. The safety profile of lacosamide during conversion to monotherapy was comparable to the safety profile described in studies of lacosamide as adjunctive therapy.

Adjunctive therapy

The efficacy of lacosamide in adjunctive therapy at recommended doses (200 mg/day, 400 mg/day) was demonstrated in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. The efficacy of lacosamide in adjunctive therapy at a dose of 600 mg/day was also shown in controlled studies, although the efficacy was comparable to the 400 mg/day dose, but the tolerability of this dose (600 mg/day) was worse due to adverse reactions from the CNS and GI tract. Therefore, the use of a 600 mg/day dose is not recommended. The maximum recommended dose is 400 mg/day. These studies involving 1308 patients with a history of partial seizures for an average of 23 years were designed to evaluate the efficacy and safety of lacosamide as an add-on to 1-3 antiepileptic drugs in patients with uncontrolled partial seizures with or without secondary generalization. The overall proportion of patients with a 50% reduction in seizure frequency in the placebo, lacosamide 200 mg/day, and lacosamide 400 mg/day groups was 23%, 34%, and 40%, respectively.

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

Primary generalized tonic-clonic seizures (PGTCS)

The efficacy of lacosamide as adjunctive therapy in patients aged 4 years and older with idiopathic generalized epilepsy suffering from PGTCS was established in a 24-week double-blind, randomized, placebo-controlled, multicenter, parallel-group study. The study consisted of a 12-week retrospective baseline period, a 4-week prospective baseline period, and a 24-week treatment period (which included a 6-week dose titration period and an 18-week dose maintenance period). Eligible patients receiving a stable dose of 1 to 3 antiepileptic drugs who had at least 3 confirmed PGTCS during the 16-week combined baseline period were randomized 1:1 to groups receiving Lacosamide or placebo (patients in the full analysis set: Lacosamide n=118, placebo n=121; of these, 8 patients in the age group from 4 to 12 years and 16 patients in the age group from 12 to 18 years received Lacosamide and 9 and 16 patients, respectively, received placebo).

Patients were gradually titrated to a target maintenance period dose of 12 mg/kg/day in patients weighing less than 30 kg, 8 mg/kg/day in patients weighing 30 to less than 50 kg, or 400 mg/day in patients weighing 50 kg and above.

Note: for the lacosamide group, the mean time to second PGTCS could not be calculated using Kaplan-Meier methods because more than 50% of patients did not experience a second PGTCS by day 166.

Results in the pediatric subgroup were consistent with the overall population results for primary, secondary, and other efficacy endpoints.

Children

The clinical manifestations of partial seizures in children over 4 years of age were comparable to those in adults. The efficacy of lacosamide in children aged 4 years and older was extrapolated from data from adolescent and adult patients with partial seizures; thus, with appropriate dose selection for children and adolescents (see “Dosage Regimen” section) and confirmation of safety (see “Adverse Reactions” section), a similar response to lacosamide therapy was expected for them. The efficacy predicted by extrapolation (see above) was confirmed by the results of clinical studies.

The initial dose was 2 mg/kg/day in patients weighing less than 50 kg or 100 mg/day in patients weighing 50 kg and above; the daily dose was divided into 2 doses. During the titration period, lacosamide doses were adjusted stepwise, increasing by 1 or 2 mg/kg/day in patients weighing less than 50 kg or by 50 or 100 mg/day in patients weighing 50 kg and above at weekly intervals to achieve the target maintenance dose.

A statistically and clinically significant reduction in the frequency of partial seizures was observed from the start of therapy to the maintenance treatment period when comparing data in the lacosamide and placebo groups. Overall, the proportion of patients with a reduction in partial seizure frequency of at least 50% over 28 days from the start of therapy to the maintenance treatment period was 52.9% in the group receiving lacosamide treatment compared to 33.3% in the placebo group.

Pharmacokinetics

Absorption

Lacosamide is rapidly and completely absorbed after oral administration. The bioavailability of lacosamide in tablets is about 100%. After oral administration, the plasma concentration of lacosamide increases rapidly, with C_max reached within 0.5-4 hours. Food intake does not affect the rate and extent of absorption.

Distribution

V_d is about 0.6 L/kg, the degree of binding to plasma proteins is less than 15%.

Metabolism

95% of lacosamide is excreted by the kidneys unchanged (about 40%) and as an O-desmethyl metabolite (less than 30%). The polar fraction (presumably serine derivatives) accounts for about 20% in urine and is found only in small amounts (0-2%) in plasma. Other metabolites are determined in urine in amounts of 0.5-2%.

In vitro data show that CYP2C9, CYP2C19, and CYP3A4 isoenzymes are capable of catalyzing the formation of the O-desmethyl metabolite, but the role of the main isoenzyme has not been confirmed in vivo. When comparing the pharmacokinetics of lacosamide in extensive metabolizers (with a functional cytochrome CYP2C19 isoenzyme) and poor metabolizers (with a deficiency of the functional CYP2C19 isoenzyme), no clinically significant difference in lacosamide excretion was noted. Furthermore, interaction studies with omeprazole (a CYP2C19 isoenzyme inhibitor) showed no clinically significant changes in lacosamide plasma concentrations, indicating the low significance of this pathway.

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

Excretion

Lacosamide is eliminated by renal excretion and biotransformation. After oral administration and intravenous administration of radiolabeled lacosamide, about 95% of the radioactivity was noted in urine and less than 0.5% in feces.

The T_1/2 of unchanged lacosamide is about 13 hours.

Pharmacokinetic parameters are dose-proportional, constant over time, and characterized by low inter-individual variability. When administered twice daily, C_ss in plasma is reached within 3 days. Accumulation is accompanied by an approximately 2-fold increase in plasma concentration.

C_ss after a single 200 mg loading dose is comparable to that after oral administration of 100 mg twice daily.

Pharmacokinetics in special patient groups

Gender. Clinical studies show that gender does not significantly affect lacosamide plasma concentrations.

Race. There are no clinically significant differences in the pharmacokinetics of lacosamide among Asian, Black, and Caucasian races.

Elderly patients. The studies included 4 patients of both sexes over 75 years of age. AUC was increased by about 30% in men and 50% in women compared to young patients. This is partly explained by reduced body weight, 26% in men and 23% in women of normal body weight. Increased excretion of lacosamide was also observed. In studies in elderly patients, the renal clearance of lacosamide was slightly reduced.

Patients with impaired renal function. The AUC value increases by approximately up to 30% in mild and moderate renal impairment and up to 60% in severe and end-stage renal disease requiring hemodialysis, compared to healthy patients, while C_max does not change. Lacosamide is removed from plasma by hemodialysis. During a 4-hour hemodialysis procedure, AUC decreases by approximately 50%. Therefore, an additional dose is recommended after the hemodialysis procedure. In patients with moderate and severe renal impairment, the excretion of the O-desmethyl metabolite increased severalfold. In patients with end-stage renal disease without hemodialysis, levels were increased and continuously increased during the 24-hour observation period. It has not been fully studied whether increased metabolite excretion in patients with end-stage renal disease can lead to an increase in adverse effects, but it has been confirmed that the O-desmethyl metabolite has no pharmacological activity.

Patients with impaired hepatic function. In patients with moderate hepatic impairment, increased plasma concentrations of lacosamide were observed (approximately 50% greater AUC_norm). One reason for the increased exposure was reduced renal function in the patients participating in the studies. The reduction in non-renal clearance in the study patients was estimated as a 20% increase in lacosamide AUC. The pharmacokinetics in patients with severe hepatic impairment have not been studied.

Children

The pharmacokinetic profile of lacosamide in children and adolescents was determined using population pharmacokinetic analysis using results from individual plasma concentration determinations obtained in clinical studies in 414 children with epilepsy aged 6 months to 17 years. Lacosamide was administered at doses from 2 to 17.8 mg/kg/day twice daily. The maximum dose for children weighing 50 kg and above was 600 mg/day. Typical plasma clearance was 1.04 L/h, 1.32 L/h, and 1.86 L/h in children weighing 20 kg, 30 kg, and 50 kg, respectively. For comparison, plasma clearance in adults weighing 70 kg was 1.92 L/h.

Population pharmacokinetic analysis using pharmacokinetic samples from a small sample from the PGTCS study showed similar exposure in patients with PGTCS and in patients with partial seizures.

Indications

For adults, adolescents and children aged 4 years and older with

• Epilepsy, as monotherapy or adjunctive therapy for partial seizures, with or without secondary generalization;
• Idiopathic generalized epilepsy – as adjunctive therapy for primary generalized tonic-clonic seizures.

ICD codes

Dosage Regimen

Tablets

Orally, regardless of meals.

The daily dose is divided into 2 doses – usually in the morning and evening.

Adolescents and children weighing 50 kg and more, and adults

The following table shows the recommended doses for adolescents and children weighing 50 kg and above, as well as for adults.

Monotherapy (for the treatment of partial seizures)

The recommended initial dose is 50 mg twice daily, which should be increased to the initial therapeutic dose of 100 mg twice daily after the 1st week.

Lacosamide treatment can also be started at a dose of 100 mg twice daily based on the physician’s assessment of the required reduction in seizure activity compared to the risk of adverse reactions.

Depending on the response and tolerability of treatment, the maintenance dose may be increased by 100 mg/day (by 50 mg twice daily) at weekly intervals, up to the maximum recommended daily maintenance dose of 600 mg/day (300 mg twice daily). If, upon reaching a dose above 400 mg/day, the patient still requires additional antiepileptic drugs, the dosing regimen for adjunctive therapy should be followed (see below).

Adjunctive therapy (for the treatment of partial seizures or primary generalized tonic-clonic seizures)

The recommended initial dose is 50 mg twice daily, which should be increased to the initial therapeutic dose of 100 mg twice daily after the 1st week.

Depending on the response and treatment tolerance, the dose may be increased by 100 mg/day (50 mg twice a day) at weekly intervals, up to the maximum recommended daily maintenance dose of 400 mg/day (200 mg twice a day).

Initiating treatment with lacosamide using a loading dose (initial monotherapy or conversion to monotherapy in the treatment of partial-onset seizures or adjunctive therapy in the treatment of primary generalized tonic-clonic seizures)

Lacosamide treatment, both as monotherapy and adjunctive therapy, may also be initiated with a single 200 mg loading dose, followed by a maintenance dosing regimen of 100 mg twice a day (200 mg/day) approximately 12 hours after the loading dose. Subsequent dose adjustment should be performed according to individual response and tolerance, as described above. A loading dose may be used in patients in situations where the physician determines that rapid attainment of steady-state plasma concentration and therapeutic effect can be achieved. Administration should be performed under medical supervision, considering the increased likelihood of severe cardiac arrhythmia and an increased number of adverse reactions from the central nervous system (see section “Adverse Reactions”). The use of a loading dose has not been studied in acute conditions, such as status epilepticus.

Missed dose

If a dose is missed, the patient should be instructed that the missed dose should be taken as soon as possible, and then the usual dosing regimen should be resumed with the next dose of lacosamide. If the patient notices the delay no earlier than 6 hours before the next dose is due, the patient should take the next dose of lacosamide according to the schedule. A double dose should not be taken.

Discontinuation of therapy

A weekly dose reduction of 4 mg/kg/day for patients weighing less than 50 kg or 200 mg/day for patients weighing more than 50 kg is required if the patient’s received dose of lacosamide was more than 6 mg/kg/day or more than 300 mg/day. A slower rate of dose reduction may be possible, involving a dose reduction of 2 mg/kg/day or 100 mg/day if the clinical situation requires it.

In cases of severe cardiac arrhythmia development, a benefit-risk analysis must be performed and, if necessary, lacosamide should be discontinued.

Special patient groups

Elderly patients

Dose reduction is not required for the elderly. In the elderly, the possibility of age-related reduction in renal clearance and, consequently, increased plasma concentration of lacosamide must be considered. Data on the use of lacosamide in elderly patients with epilepsy, especially at doses above 400 mg/day, are limited (see sections “Pharmacodynamics”, “Special warnings and precautions for use”, “Adverse Reactions”).

Patients with renal impairment

Adult patients and children with mild to moderate renal impairment (CrCl > 30 ml/min) do not require dose adjustment. Children weighing 50 kg and more, as well as adult patients with mild to moderate renal impairment, may be prescribed a loading dose of 200 mg, but further dose titration (>200 mg/day) should be performed with caution. For children weighing 50 kg and more, as well as for adult patients with severe renal impairment (CrCl ≤30 ml/min) and for patients with end-stage renal disease, the recommended maximum dose is 250 mg/day. In these patients, dose titration should be performed with caution. If a loading dose is indicated, the initial dose is 100 mg followed by 50 mg twice a day during the first week. For children weighing less than 50 kg with severe renal impairment (CrCl ≤30 ml/min) or end-stage renal disease, a 25% reduction in the maximum dose is recommended.

For all patients undergoing hemodialysis, an additional 50% of the single dose is recommended to be administered immediately after the procedure. Treatment of patients with end-stage renal disease should be conducted with caution, as the clinical experience with the drug in such patients is limited, and accumulation of a metabolite with unspecified pharmacological activity is possible.

Patients with hepatic impairment

For adult patients and children weighing 50 kg and more with mild to moderate hepatic impairment, the maximum dose is 300 mg/day.

Dose titration in such patients should be performed with caution, considering that hepatic impairment is often accompanied by renal impairment. Adolescents and adults weighing 50 kg and more may be prescribed a loading dose of 200 mg, but further dose titration (>200 mg/day) is recommended to be performed with caution. Based on data from adult patients, adolescents and children with mild to moderate hepatic impairment weighing less than 50 kg require a 25% reduction in the maximum dose.

The pharmacokinetics of lacosamide in patients with severe hepatic impairment have not been studied (see section “Pharmacokinetics”).

Lacosamide should be prescribed to adult patients, as well as adolescents and children with severe hepatic impairment, only when the expected therapeutic benefit of the drug outweighs the likely risks of its use. Dose adjustment may be required based on disease activity and the emergence of potential adverse reactions in the patient.

Children

The physician should prescribe the most appropriate pharmaceutical form and dosage depending on the patient’s body weight and the recommended dose.

Adolescents and children weighing 50 kg and more

The dosing regimen for adolescents and children weighing 50 kg and more does not differ from the dosing regimen for adults (see above).

Children (over 4 years old) and adolescents weighing less than 50 kg

The dose is determined based on body weight, therefore it is recommended to initiate treatment with an oral solution, and then switch to tablets (if desired).

Monotherapy (in the treatment of partial-onset seizures)

The recommended initial dose is 2 mg/kg/day, which should be increased to the initial therapeutic dose of 4 mg/kg/day after the first week.

Depending on the response and treatment tolerance, the maintenance dose may be further increased by 2 mg/kg/day at weekly intervals. The dose should be increased gradually until an optimal response is obtained. In children weighing less than 40 kg, the maximum recommended dose is 12 mg/kg/day. In children weighing from 40 to 50 kg, the maximum recommended dose is 10 mg/kg/day.

The following table shows the recommended doses for monotherapy in children and adolescents weighing less than 50 kg.

Adjunctive therapy (in the treatment of partial-onset or primary generalized tonic-clonic seizures)

The recommended initial dose is 2 mg/kg/day, which should be increased to the initial therapeutic dose of 4 mg/kg/day after the first week.

Depending on the response and treatment tolerance, the maintenance dose may be further increased by 2 mg/kg/day at weekly intervals. The dose should be increased gradually until an optimal response is obtained. In children weighing less than 20 kg, due to higher clearance compared to adult patients, the maximum recommended dose is up to 12 mg/kg/day. In children weighing from 20 to 30 kg, the maximum recommended dose is 10 mg/kg/day, and in children weighing from 30 to 50 kg, the maximum recommended dose is 8 mg/kg/day, although in open-label studies (see sections “Pharmacokinetics” and “Adverse Reactions”) a dose within 12 mg/kg/day was administered only to a small number of children.

The following table shows the recommended doses for adjunctive therapy in children and adolescents weighing up to 50 kg.

Loading dose

The use of a loading dose in children has not been studied. The use of a loading dose is not recommended in adolescents and children weighing less than 50 kg.

Children under 4 years of age

The safety and efficacy of lacosamide in children under 4 years of age have not been established. No data are available.

When taken orally, the initial dose is 50 mg twice a day. Depending on efficacy and tolerance, the dose is gradually increased. The maximum daily dose is 400 mg (200 mg twice a day). Treatment should be discontinued by gradually reducing the dose.

Adverse Reactions

Summary of the safety profile

Based on an analysis of pooled placebo-controlled clinical trials of adjunctive therapy, which included 1308 patients with partial-onset seizures, 61.9% of patients randomized to the lacosamide group and 35.2% of patients randomized to the placebo group reported at least one adverse reaction. The most frequent adverse reactions (≥10%) with lacosamide were dizziness, headache, nausea, and diplopia. They were generally mild or moderate in severity. The severity of some adverse reactions was dose-dependent and decreased after dose reduction. The frequency and severity of central nervous system and gastrointestinal adverse reactions usually decreased over time.

In all controlled clinical trials, the frequency of therapy discontinuation due to adverse reactions was 12.2% for patients randomized to the lacosamide group and 1.6% for patients randomized to the placebo group. The most frequent adverse reaction leading to discontinuation of lacosamide therapy was dizziness. The proportion of central nervous system adverse reactions, such as dizziness, may be higher after the use of a loading dose.

Based on the analysis of data from a clinical trial of lacosamide monotherapy efficacy compared with carbamazepine (controlled-release), the most frequent adverse reactions (≥10%) with lacosamide were headache and dizziness. The frequency of therapy discontinuation due to adverse reactions was 10.6% for patients taking Lacosamide and 15.6% for patients taking carbamazepine (controlled-release).

The safety profile of lacosamide recorded in the study in patients aged 4 years and older with idiopathic generalized epilepsy with primary generalized tonic-clonic seizures (PGTCS) was consistent with the safety profile obtained in pooled placebo-controlled clinical trials for partial-onset seizures. Additional adverse reactions recorded in patients with PGTCS were myoclonic epilepsy (2.5% in the lacosamide group and 0% in the placebo group) and ataxia (3.3% in the lacosamide group and 0% in the placebo group). The most frequent adverse reactions were dizziness and somnolence. The most common adverse reactions leading to discontinuation of lacosamide therapy were dizziness and suicidal thoughts. The proportion of patients who discontinued therapy due to the occurrence of adverse reactions was 9.1% in the lacosamide group and 4.1% in the placebo group.

Tabulated summary of adverse reactions

Adverse reactions noted during clinical trials and in post-marketing experience, with their frequencies, are presented in the table by system organ class according to the Medical Dictionary for Regulatory Activities (MedDRA) classification. Classification of the frequency of adverse reactions according to WHO recommendations: very common (≥1/10), common (≥1/100, but <1/10), uncommon (≥1/1000, but <1/100), rare (≥1/10000, but <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data). Within each category, adverse reactions are presented in descending order of severity.

¹– adverse reactions identified in post-marketing experience.

²– see subsection “Description of selected adverse reactions”.

³– reported in PGTCS studies.

Description of selected adverse reactions

The use of lacosamide is associated with a dose-dependent prolongation of the PR interval. Adverse reactions associated with PR interval prolongation (e.g., atrioventricular block, syncope, bradycardia) may be observed.

In adjunctive therapy clinical trials in patients with epilepsy, the percentage of first-degree atrioventricular block episodes was low – 0.7%, 0%, 0.5%, and 0% with lacosamide at doses of 200 mg, 400 mg, 600 mg, and placebo, respectively. Second-degree or higher atrioventricular block was not observed in these studies. However, cases of second- and third-degree atrioventricular block have been reported in post-marketing experience during treatment with lacosamide. In a comparative clinical trial of lacosamide monotherapy compared with carbamazepine (controlled-release), the increase in PR interval was comparable for both drugs.

Syncope in lacosamide adjunctive therapy clinical trials was uncommon, and the percentage of episodes did not differ between groups of patients with epilepsy receiving Lacosamide (n=944) (0.1%) and receiving placebo (0.3%). In clinical trials of lacosamide monotherapy efficacy compared with carbamazepine (controlled-release), syncope was observed in 7 out of 444 (1.6%) patients receiving Lacosamide, and in 1 out of 442 (0.2%) patients receiving carbamazepine (controlled-release).

Atrial fibrillation and atrial flutter were not noted in short-term clinical trials; however, both phenomena have been noted in open-label epilepsy studies and in post-marketing experience.

Laboratory abnormalities

Changes in liver function tests were noted in placebo-controlled trials of lacosamide in adult patients with partial-onset seizures using 1 to 3 concomitant antiepileptic drugs. An increase in ALT of 3 times or more was observed in 0.7% (7 out of 935) of patients taking Lacosamide and in 0% (0 out of 356) of patients taking placebo.

Hypersensitivity reactions with multiorgan involvement

Hypersensitivity reactions with multiorgan involvement (also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)) have been noted in patients receiving some antiepileptic drugs. These reactions vary in manifestation but most often present as fever and rash and may involve other systems. If a hypersensitivity reaction with multiorgan involvement is suspected, lacosamide should be discontinued.

Elderly patients

In a comparative study of lacosamide monotherapy and carbamazepine (controlled-release), the types of adverse reactions in elderly patients (over 65 years) were the same as those observed in patients under 65 years. However, in elderly patients compared with younger adults, a higher frequency (difference ≥5%) was observed for the following adverse reactions: falls, diarrhea, and tremor. The most frequent cardiovascular adverse reaction in elderly patients compared with younger patients was first-degree atrioventricular block. It was observed during lacosamide therapy in 4.8% (3 out of 62) of elderly patients compared with 1.6% (6 out of 382) of younger adult patients; for carbamazepine (controlled-release), the corresponding values were 5.3% (3 out of 57) in elderly patients and 1.3% (5 out of 385) in younger adult patients. The frequency of adverse events observed in elderly patients during lacosamide therapy was 21.0% (13 out of 62) compared with 9.2% (35 out of 382) in younger adult patients. These differences between elderly and younger adult patients were similar to those observed in the comparator drug group.

Children

The safety profile of lacosamide in placebo-controlled (see section “Pharmacodynamics”) and open-label clinical trials (n=408) during adjunctive therapy in children with partial-onset seizures over 4 years of age was consistent with that in adults, although the frequency of some adverse reactions (somnolence, vomiting, and convulsions) was increased. In children and adolescents, additional adverse reactions also appeared (nasopharyngitis, pyrexia, pharyngitis, decreased appetite, lethargy, and behavior disorder): nasopharyngitis (15.7%), vomiting (14.7%), somnolence (14.0%), dizziness (13.5%), pyrexia (13.0%), convulsions (7.8%), decreased appetite (5.9%), pharyngitis (4.7%), lethargy (2.7%), and behavior disorder (1.7%). In total, at least one adverse reaction was reported in 67.8% of patients randomized to receive Lacosamide and in 58.1% of patients randomized to receive placebo.

Contraindications

• Hypersensitivity to lacosamide or to any of the excipients included in the drug formulation;
• Second- or third-degree atrioventricular block;
• Children under 4 years of age.

With caution in patients with severe renal impairment (CrCl ≤30 ml/min).

Use in Pregnancy and Lactation

Women of childbearing potential

Physicians should discuss aspects of family planning and contraception with women of childbearing potential taking Lacosamide (see subsection “Pregnancy”).

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

Pregnancy

Overall risk associated with epilepsy and antiepileptic drugs

All antiepileptic drugs have been shown to be associated with a 2-3 times higher frequency of congenital malformations in children of women with epilepsy receiving such therapy compared to the general population (where the rate is 3%). An increased frequency of congenital malformations in children has been observed in patients receiving polytherapy; however, the extent of the influence of treatment and/or the disease on this increased risk is currently unknown.

Furthermore, effective antiepileptic treatment should not be discontinued, as worsening of the disease has a negative impact on both the mother and the fetus.

Risk associated with lacosamide use

There are no clinical data on the use of lacosamide in pregnant women. Animal studies have not revealed teratogenic effects, but embryotoxicity was observed in rabbits and rats at doses toxic to the maternal organism. The potential risk to humans is unknown.

Lacosamide should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the fetus. If a woman is planning a pregnancy, the advisability of using this drug should be carefully weighed. To monitor the consequences of using Novolera^® EPI in pregnant women, physicians are encouraged to register patient data in the International Registry of Antiepileptic Drugs and Pregnancy (EURAP).

Breastfeeding period

Lacosamide is excreted in breast milk.

Risks to newborns and infants cannot be ruled out.

Breastfeeding should be discontinued during treatment with lacosamide.

Fertility

No effect of lacosamide on fertility or reproductive function was observed in male or female rats at doses producing plasma concentrations (AUC) approximately 2 times higher than the human plasma AUC at the maximum recommended human dose.

Use in Hepatic Impairment

Lacosamide should be administered to adult patients with severe hepatic impairment only when the expected therapeutic benefit of the drug outweighs the likely risks of its use. Dose adjustment may be required based on disease activity and the emergence of potential adverse reactions in the patient.

Use in Renal Impairment

No dose adjustment is required for adult patients with mild to moderate renal impairment (CrCl > 30 ml/min). Dose adjustment is required for adult patients with severe renal impairment (CrCl ≤30 ml/min) and for patients with end-stage renal disease. Treatment of patients with end-stage renal disease should be conducted with caution, as clinical experience with the drug in such patients is limited, and accumulation of a metabolite with unspecified pharmacological activity is possible.

Pediatric Use

The use of the drug in children under 4 years of age is contraindicated (the safety and efficacy of lacosamide in children under 4 years of age have not been established).

Geriatric Use

No dose reduction is required for elderly patients.

Special Precautions

Suicidal thoughts and behavior

Suicidal thoughts and behavior have been observed in patients treated with antiepileptic drugs for several indications. A meta-analysis of randomized, placebo-controlled clinical trials of antiepileptic drugs indicates a small increased risk of suicidal thoughts and suicidal behavior. The mechanism for this increased risk is unclear, and the available data do not rule out the existence of such a risk with lacosamide. Therefore, patients should be monitored for signs of suicidal thoughts and behavior, and appropriate treatment should be considered. Patients and caregivers should be advised of the existing risk and the need to consult a specialist if suicidal behavior occurs.

Cardiac rhythm and conduction

Clinical studies of lacosamide have described a dose-dependent increase in the PR interval. Lacosamide should be used with caution in patients with proarrhythmic conditions, such as known history of cardiac conduction disorders, or with severe cardiac disease in their history (e.g., myocardial ischemia/infarction, heart failure, structural heart disease, or cardiac sodium channelopathies) or in patients receiving medications that affect cardiac conduction, including antiarrhythmic agents and antiepileptic drugs from the sodium channel blocker group, as well as in elderly patients with an increased risk of heart disease.

Such patients should have an ECG performed before increasing the lacosamide dose above 400 mg/day, and after reaching a stable concentration.

In placebo-controlled studies of lacosamide in patients with epilepsy, atrial fibrillation or flutter was not observed; however, both phenomena were identified in patients with epilepsy in open-label clinical studies and in the analysis of post-marketing experience.

Cases of atrioventricular block (including second-degree atrioventricular block) have been observed in post-marketing practice. Ventricular tachyarrhythmia has been observed in patients with proarrhythmic conditions. In rare cases, these events have led to asystole, cardiac arrest, and death in patients with underlying proarrhythmic conditions.

Patients should be informed about the symptoms of cardiac arrhythmia (e.g., slow, fast, or irregular pulse, palpitations, shortness of breath, dizziness, fainting). If they occur, a doctor should be consulted.

Dizziness

Treatment with lacosamide may be accompanied by dizziness, potentially leading to an increased risk of injury or falls. Therefore, patients should exercise caution until it is determined what potential adverse reactions they may develop.

Possible occurrence or exacerbation of myoclonic seizures

The occurrence or exacerbation of myoclonic seizures has been reported in both adults and children with primary generalized tonic-clonic seizures, particularly during titration. In patients with two or more types of seizures, the observed improvement in control of one seizure type should be weighed against any observed worsening of another seizure type.

Effect on ability to drive and use machines

The degree of effect of lacosamide on the ability to drive vehicles and operate machinery varies from minor to moderate. Treatment with lacosamide may be accompanied by dizziness or blurred vision. Patients are advised not to drive vehicles or engage in other activities requiring concentration.

Overdose

Symptoms

Symptoms following accidental or intentional overdose of lacosamide were predominantly due to central nervous system and gastrointestinal involvement.

The types of adverse reactions in patients taking Lacosamide at doses from 400 to 800 mg and taking recommended doses of lacosamide were not clinically different.

Reactions noted after taking lacosamide at doses above 800 mg included dizziness, nausea, vomiting, epileptic seizures (generalized tonic-clonic convulsions, status epilepticus). Cardiac conduction disorders, shock, and coma were also noted. Fatal outcomes have been reported in patients following acute overdose of several grams of lacosamide.

Treatment

There is no antidote for lacosamide. Treatment of overdose is symptomatic. Hemodialysis may be used if necessary.

Drug Interactions

Lacosamide should be used cautiously in combination with drugs that cause PR interval prolongation (including sodium channel blocking drugs) and Class I antiarrhythmic drugs. However, a subgroup analysis of clinical studies did not reveal additional PR interval prolongation in patients who were simultaneously taking Lacosamide in combination with carbamazepine or lamotrigine.

In vitro data

Study results suggest a low likelihood of interaction between lacosamide and other drugs.

In vitro metabolism studies show that Lacosamide does not induce cytochrome P450 (CYP) isoenzymes 1A2, 2B6, and 2C9. At concentrations measured in blood during clinical studies, Lacosamide did not inhibit CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, and 2E1 isoenzymes. In vitro studies suggest that Lacosamide is not transported by P-glycoprotein in the intestine. In vitro data indicate that CYP2C9, CYP2C19, and CYP3A4 isoenzymes are capable of catalyzing the formation of the O-desmethyl metabolite.

In vivo data

Clinical data indicate that Lacosamide does not inhibit or induce CYP2C19 and 3A4 isoenzymes to a clinically significant level.

Lacosamide had no effect on the AUC of midazolam (metabolized via CYP3A4 isoenzyme, at a lacosamide dosage of 200 mg twice daily), but the C_max of midazolam was slightly increased (30%). Lacosamide does not affect the pharmacokinetics of omeprazole (metabolized via CYP2C19 and 3A4 isoenzymes, at a lacosamide dose of 300 mg twice daily).

Omeprazole, a CYP2C19 isoenzyme inhibitor (40 mg four times daily), did not increase the exposure to lacosamide to a clinically significant extent. Thus, it is unlikely that moderate inhibitors of the CYP2C19 isoenzyme can affect the systemic exposure of lacosamide to a clinically significant level.

Caution should be exercised when co-administering with potent inhibitors of the CYP2C19 isoenzyme (e.g., fluconazole) and the CYP3A4 isoenzyme (e.g., itraconazole, ketoconazole, ritonavir, clarithromycin), as this may lead to increased systemic exposure to lacosamide. These interactions have not been established in vivo but are possible based on in vitro data.

Potent inducers of hepatic microsomal enzymes, such as rifampicin or St. John’s wort (Hypericum perforatum), may cause a moderate decrease in systemic lacosamide concentration. Therefore, caution should be exercised when prescribing or discontinuing such drugs.

Antiepileptic drugs

In interaction studies, Lacosamide did not significantly affect the plasma concentrations of carbamazepine and valproic acid. Carbamazepine and valproic acid did not affect the plasma concentration of lacosamide.

Based on a population pharmacokinetic analysis, it was concluded that concomitant therapy with antiepileptic drugs that induce hepatic microsomal enzymes (carbamazepine, phenytoin, phenobarbital at various doses) reduced the total systemic exposure to lacosamide by 25% in adult patients and by 17% in children and adolescents.

Oral contraceptives

No evidence of significant interaction between lacosamide and oral contraceptives containing ethinyl estradiol and levonorgestrel was found. Lacosamide does not affect progesterone concentration.

Other interactions

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

There are no data on the interaction of lacosamide with alcohol.

The extent of lacosamide binding to plasma proteins is less than 15%. Therefore, a clinically significant interaction with other drugs that bind to plasma proteins is unlikely.

When used concomitantly with warfarin, Lacosamide does not have a clinically significant effect on the pharmacodynamics and pharmacokinetics of warfarin.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.