Instructions for Lakozam tablets 100 mg No. 56
Composition
active ingredient: lacosamide;
1 tablet contains lacosamide 50 mg or 100 mg;
excipients: microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, hydroxypropylcellulose, colloidal anhydrous silicon dioxide, magnesium stearate;
shell: polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, red iron oxide (E 172), black iron oxide (E 172), FD&C blue #2/indigo carmine aluminum lake (E 132) (for 50 mg dosage);
shell: polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, yellow iron oxide (E 172), black iron oxide (E 172) (for 100 mg dosage).
Dosage form
Film-coated tablets.
Main physicochemical properties:
50 mg tablets: pink, oblong, biconvex, film-coated tablets, embossed with “50” on one side and plain on the other side;
100 mg tablets: yellow, oblong, biconvex, film-coated tablets, debossed with “100” on one side and plain on the other side.
Pharmacotherapeutic group
Other antiepileptic drugs.
ATX code N03A X18.
Pharmacological properties
Mechanism of action
The active ingredient 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 vitro electrophysiological studies have shown that lacosamide selectively enhances the slow inactivation of voltage-gated sodium channels, which leads to the stabilization of hyperexcitable neuronal membranes.
Pharmacodynamics.
The anticonvulsant efficacy of lacosamide has been demonstrated in various animal studies with partial and primary generalized seizures and delayed kindling (epileptogenic effect in experimental animals). In preclinical studies, lacosamide has shown synergistic or additive anticonvulsant effects 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) has been established in three multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. The efficacy of lacosamide 600 mg/day has also been established in controlled adjunctive therapy trials, although the efficacy of this dose was the same as that of 400 mg/day, and patients tolerated the lower dose better because of the CNS and gastrointestinal adverse reactions associated with 600 mg/day. Therefore, a dose of 600 mg/day is not recommended. The maximum recommended dose is 400 mg/day. The aim of these studies, which included 1308 patients with a mean history of partial-onset seizures of 23 years, was to evaluate the efficacy and safety of lacosamide in combination with 1 to 3 other antiepileptic drugs in patients with uncontrolled partial-onset seizures with or without secondary generalization. Overall, the percentage of patients achieving a 50% reduction in seizure frequency was 23%, 34%, and 40% for placebo, 200 mg, and 400 mg lacosamide daily, respectively.
There are insufficient data on the withdrawal of concomitant antiepileptic drug treatment in order to achieve success with lacosamide monotherapy.
The pharmacokinetics and safety of a single intravenous loading dose of lacosamide were determined in a multicenter, open-label study to evaluate the safety and tolerability of abrupt initiation of lacosamide with a single intravenous loading dose (200 mg inclusive) followed by twice daily oral administration (equivalent to the intravenous dose) as adjunctive therapy in adult patients aged 16 to 60 years with partial onset seizures.
Pharmacokinetics.
Absorption
Lacosamide is rapidly and completely absorbed after oral administration. The bioavailability of lacosamide in tablets is approximately 100%. After oral administration, the concentration of unchanged lacosamide in the blood plasma increases rapidly, Cmax is reached after 0.5-4 hours. The dosage forms of lacosamide, film-coated tablets and oral syrup, are bioequivalent. Food does not affect the rate and extent of absorption.
Distribution
The volume of distribution is approximately 0.6 l/kg, the degree of binding to plasma proteins is less than 15%.
Biotransformation
95% of the dose is excreted in the urine as lacosamide and metabolites. The metabolism of lacosamide is not fully understood.
The main compounds excreted in the urine are unchanged lacosamide (approximately 40% of the dose) and its O-desmethyl metabolite (less than 30%).
The proportion of the polar fraction in urine (presumably serine derivatives) was approximately 20%, but it was detected only in small amounts (0-2%) in the plasma of some patients. Small amounts of other metabolites detected in urine are 0.5-2%.
O-desmethyl metabolite, but the role of the main isoenzyme involved has not been confirmed in vivo. No clinically relevant differences in lacosamide exposure were observed when comparing its pharmacokinetics in extensive metabolizers (EMs, individuals with functional CYP2C19) and poor metabolizers (PMs, individuals with functional CYP2C19 deficiency). Moreover, interaction studies with omeprazole (a CYP2C19 inhibitor) showed no clinically relevant changes in lacosamide plasma concentrations, indicating a minimal role for this metabolic pathway.
The plasma concentration of the O-desmethyl metabolite is approximately 15% of that of lacosamide. This major metabolite has no known pharmacological activity.
Breeding
Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. Following oral and intravenous administration of radiolabeled lacosamide, approximately 95% of the radioactivity was recovered in the urine and less than 0.5% in the feces. The elimination half-life of unchanged drug is approximately
13 hours. Pharmacokinetics are dose-proportional, do not change over time and are characterized by low inter- and intra-individual variability. When administered twice daily, steady-state plasma concentrations are reached within 3 days. Cumulation is accompanied by an increase in plasma concentrations of approximately 2 times.
The use of a single loading dose of 200 mg brings the equilibrium concentration of the drug in the blood plasma closer to that which is comparable to the use of the drug orally at a dose of 100 mg 2 times a day.
Pharmacokinetics in special patient groups
Sex
Clinical studies have shown that gender has no clinically significant effect on lacosamide plasma concentrations.
Kidney dysfunction
The AUC of lacosamide was increased by approximately 30% in patients with mild to moderate renal impairment, by 60% in patients with severe renal impairment and in patients with end-stage renal disease requiring haemodialysis. However, these conditions did not affect Cmax.
Lacosamide is effectively removed from plasma by haemodialysis. After 4 hours of haemodialysis, the AUC of lacosamide is reduced by approximately 50%. Therefore, it is recommended to increase the dose of the drug after haemodialysis. The exposure of the O-desmethyl metabolite increases several-fold in patients with moderate to severe renal impairment. When haemodialysis was not performed in patients with end-stage renal disease, these values were elevated and continuously increased, as seen in analyses performed over 24 hours. It is not known whether the increased exposure of the drug metabolite in patients with end-stage renal disease could lead to adverse reactions, but no pharmacological activity of this metabolite was detected.
Liver dysfunction
In patients with moderate hepatic impairment (Child-Pugh class B), increased lacosamide concentrations (approximately 50% higher than AUCnorm) were observed. The increased exposure was partly due to reduced renal function in the patients studied. The reduced non-renal clearance in the patients studied resulted in a 20% increase in lacosamide AUC. The pharmacokinetics of lacosamide in patients with severe hepatic impairment have not been studied.
Elderly patients (65 years and older)
In studies conducted with elderly women and men and including
In 4 patients aged 75 years and older, AUC was approximately 30% and 50% higher compared to younger patients, respectively. This result is partly due to lower body weight. This difference is 26% and 23%, respectively, for the combined difference in body weight. There was also increased variability in the patient exposure. In this study, it was found that renal clearance of lacosamide was only slightly reduced in elderly patients.
The total dose of the drug should not be reduced unless indicated due to decreased renal function.
Indication
As adjunctive therapy for the treatment of partial seizures, with or without secondary generalization, in patients aged 16 years and older with epilepsy.
Contraindication
Hypersensitivity to the active substance or to excipients.
History of second or third degree atrioventricular block.
Interaction with other medicinal products and other types of interactions
Lacosamide should be used with caution in patients receiving medicinal products known to prolong the PR interval (including antiepileptic medicinal products - sodium channel blockers) and in patients receiving class I antiarrhythmic medicinal products. However, in subgroup analyses in clinical trials, no additional prolongation of the PR interval was observed in patients receiving lacosamide concomitantly with carbamazepine or lamotrigine.
Overall, the results of the studies indicate that the potential for interactions of lacosamide with other medicinal products is low. In vitro studies show that lacosamide does not induce CYP1A2, 2B6 and 2C9 enzymes and does not inhibit CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6 and 2E1 at plasma concentrations used in clinical studies. In vitro studies have shown that lacosamide is not transported by P-glycoprotein in the intestine. In vitro data indicate that CYP2C9, CYP2C19 and CYP3A4 are capable of catalyzing the formation of the O-desmethyl metabolite.
In vivo data
In vivo, lacosamide does not inhibit or induce CYP2C19 and 3A4 enzymes to a clinically relevant extent.
Lacosamide did not affect the AUC of midazolam (metabolized by CYP3A4, lacosamide was administered at a dose of 200 mg twice daily), but the Cmax of midazolam was slightly increased (30%). Lacosamide did not affect the pharmacokinetics of omeprazole (metabolized by CYP2C19 and 3A4, lacosamide was administered at a dose of 300 mg twice daily).
The CYP2C19 inhibitor omeprazole (40 mg once daily) did not cause clinically significant changes in lacosamide exposure. Therefore, moderately potent CYP2C19 inhibitors are unlikely to affect the systemic exposure of lacosamide to a clinically relevant extent.
Caution is advised when co-administering potent inhibitors of CYP2C9 (e.g. fluconazole) and CYP3A4 (e.g. itraconazole, ketoconazole, ritonavir, clarithromycin) as this may increase systemic exposure to lacosamide. Such interactions have not been established in vivo, but are likely based on in vitro data.
Strong enzyme inducers such as rifampicin or St. John's wort (Hypericum perforatum) may cause a modest decrease in systemic exposure to lacosamide. Therefore, caution should be exercised when prescribing or withdrawing such medicinal products.
Antiepileptic drugs
Lacosamide did not significantly alter plasma concentrations of carbamazepine and valproic acid. In turn, carbamazepine and valproic acid did not affect plasma levels of lacosamide. According to a population pharmacokinetic analysis, concomitant therapy with other enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, phenobarbital at various doses) reduced the total systemic exposure of lacosamide by 25%.
Oral contraceptives
An interaction study showed no evidence of a clinically significant interaction between lacosamide and the oral contraceptives ethinylestradiol and levonorgestrel. Progesterone concentrations were not altered by co-administration of the drugs.
Others
Lacosamide did not affect the pharmacokinetics of digoxin. No clinically significant interaction between lacosamide and metformin was observed.
Concomitant use of warfarin with lacosamide did not reveal clinically significant results in the pharmacokinetics and pharmacodynamics of warfarin.
Although pharmacokinetic data on the interaction of lacosamide with alcohol are lacking, a pharmacodynamic effect cannot be excluded.
The degree of protein binding of lacosamide is low, less than 15%. Therefore, clinically significant interactions with other drugs that are bound to blood proteins are unlikely.
Application features
Dizziness
Lacosamide treatment is associated with dizziness, which may lead to an increased incidence of accidental injury and falls. Therefore, patients should be warned about the possible effects of the drug and caution should be advised.
Heart rhythm and conduction
In clinical studies, a dose-dependent prolongation of the PR interval was observed with lacosamide. Lacosamide should be used with caution in patients with known proarrhythmic conditions such as cardiac conduction disorders or serious cardiac disease (e.g. myocardial ischemia/infarction, heart failure, structural heart disease or cardiac sodium channel pathology) or when patients are taking medicinal products that affect cardiac conduction, including antiarrhythmics and antiepileptics - sodium channel blockers, and in elderly patients.
Atrial fibrillation or flutter was not reported in placebo-controlled studies of lacosamide in patients with epilepsy, however, such reports have been received in open-label epilepsy studies and during post-marketing surveillance.
During post-marketing surveillance, reports of second-degree or higher degree atrioventricular block have been received. Ventricular tachyarrhythmias have been reported in patients with proarrhythmic conditions. Rarely, these events have resulted in asystole, cardiac arrest, or death in patients with known proarrhythmic conditions.
Patients should be advised of 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 these symptoms occur.
Suicidal ideation and behavior have been observed in patients receiving antiepileptic drugs for a variety of conditions. A meta-analysis of randomized, placebo-controlled clinical trials of antiepileptic drugs also showed a small increased risk of suicidal ideation and behavior. The mechanism of this risk is unknown, and the available data do not exclude the possibility of an increased risk with lacosamide.
Therefore, patients should be monitored for signs of suicidal thinking and behavior and treated as necessary. Patients (and caregivers of patients) should be advised to seek medical advice if signs of suicidal thinking and behavior emerge.
Use during pregnancy or breastfeeding
Pregnancy
Risk associated with epilepsy and the use of antiepileptic drugs in general: in newborns of mothers treated for epilepsy, the incidence of congenital malformations is 2-3 times higher than in the general population (approximately 3%). Polytherapy of pregnant women has been associated with an increased incidence of congenital malformations in children, but it remains unclear to what extent this is related to the treatment and/or to the disease itself. Furthermore, effective antiepileptic therapy should not be interrupted during pregnancy, as worsening of the disease can have serious consequences for both the mother and the fetus.
Risk associated with the use of lacosamide: There are no adequate data on the use of lacosamide in pregnant women. Animal studies (rats and rabbits) did not reveal teratogenic effects of the drug, but embryotoxicity was observed when the drug was administered at maternally toxic doses. The potential risk to humans is unknown. Lacosamide should not be used in pregnant women unless the treatment is clearly necessary (if the benefit to the mother clearly outweighs the potential risk to the fetus). If a woman is planning a pregnancy, the appropriateness of using this drug should be carefully considered.
Breast-feeding
There is no information on the excretion of lacosamide in breast milk. A risk to the newborn/infant cannot be excluded. Animal studies have shown that lacosamide is excreted in breast milk. As a precautionary measure, breast-feeding should be discontinued during treatment with lacosamide.
Fertility
No adverse effects on fertility and reproductive function in male and female rats were observed at doses with plasma exposures (AUC) approximately 2 times higher than the human plasma AUC at the maximum recommended dose.
Ability to influence reaction speed when driving vehicles or other mechanisms
Lacosamide has minor to moderate influence on the ability to drive or use machines. Dizziness or blurred vision has been reported during treatment with this drug. Accordingly, patients are advised not to drive or operate machinery until their individual response to lacosamide is known.
Method of administration and doses
Lacosamide should be taken twice daily (usually once in the morning and once in the evening). If a dose is missed, the patient should be advised to take the missed dose as soon as possible and then take the next dose of lacosamide at the usual time. If the patient notices that a dose has been missed within 6 hours of the next dose, he/she should be advised to wait and take the next dose of lacosamide as usual. Patients should not take a double dose.
The recommended initial dose is 50 mg twice daily. After 1 week, the dose should be increased to the initial therapeutic dose of 100 mg twice daily.
Depending on therapeutic response and tolerability, the maintenance dose may be further increased at weekly intervals by 50 mg twice daily (100 mg daily) to a maximum recommended daily dose of 400 mg (200 mg twice daily).
Starting lacosamide treatment with a loading dose
The drug can also be started 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). Further dose adjustments should be made according to individual response and tolerability as described above. A loading dose may be used in patients in whom the physician believes that rapid achievement of steady-state plasma lacosamide concentrations and therapeutic benefit are warranted. Administration should be under medical supervision, taking into account the potential for an increased incidence of serious cardiac arrhythmias and central nervous system adverse reactions (see section 4.8). The administration of a loading dose has not been studied in acute conditions such as status epilepticus.
Discontinuation of use
In accordance with current clinical practice, it is recommended to discontinue the drug Lakozam® gradually (reducing the dose by 200 mg per week).
For patients who develop serious cardiac arrhythmia, a clinical benefit/risk assessment should be performed and lacosamide discontinued if necessary.
Special populations
No dose reduction is required in elderly patients. Experience with lacosamide in elderly patients with epilepsy is limited. For elderly patients, the possibility of age-related decrease in renal clearance and increase in AUC should be considered (see sections “Use in patients with renal impairment” and “Pharmacokinetics”).
Use in patients with renal impairment
No dose adjustment is required for patients with mild or moderate renal impairment (creatinine clearance > 30 ml/min).
A loading dose (200 mg) may be used in patients with mild to moderate renal impairment, but subsequent dose titration (> 200 mg/day) should be performed with caution. A maximum dose of 250 mg/day is recommended in patients with severe renal impairment (creatinine clearance ≤ 30 ml/min) and in patients with end-stage renal disease. Dose titration should be performed with caution in such patients. If a loading dose is prescribed, a single initial dose of 100 mg/day should be administered, followed by 50 mg twice daily for the first week.
Patients undergoing hemodialysis are recommended to administer an additional 50% of the divided daily dose immediately at the end of the procedure. Treatment of patients with end-stage renal disease should be carried out with caution, as clinical experience with the drug in such patients is limited and accumulation of a metabolite with no known pharmacological activity is possible.
Use in patients with hepatic impairment
A maximum dose of 300 mg/day is recommended for patients with mild or moderate hepatic impairment.
Dose titration in such patients should be done with caution, taking into account the possibility of concomitant renal impairment. A loading dose (200 mg) may be considered, but subsequent dose titration (> 200 mg daily) should be performed with caution. The pharmacokinetics of lacosamide have not been studied in patients with severe hepatic impairment. Lacosamide should be used in patients with severe hepatic impairment only if the expected therapeutic benefit outweighs the potential risks. Dose adjustments may be necessary based on careful monitoring of disease activity and the patient’s potential for adverse reactions.
Use in children
The drug is not recommended for use in children under 16 years of age, as the safety and efficacy of the drug in these age groups have not been studied.
Method of application
Lacosamide, film-coated tablets, are for oral use. Lacosamide can be taken with or without food.
Children
The drug is not recommended for use in children under 16 years of age, as the safety and effectiveness of the drug in these age groups have not been studied.
Overdose
Symptoms
Symptoms observed after accidental or intentional overdose of lacosamide are primarily related to the CNS and gastrointestinal tract.
· There were no clinically significant differences between the type of adverse reactions observed in patients receiving doses above 400 mg and up to 800 mg and those observed in patients receiving therapeutic doses of lacosamide.
· Reactions reported after taking more than 800 mg are dizziness, nausea, vomiting, seizures (generalized tonic-clonic seizures, status epilepticus). Cardiac conduction disturbances, shock and coma have also been observed. Fatalities have been reported in patients after acute single overdose (intake of several grams of lacosamide).
Treatment
There is no specific antidote for lacosamide overdose. Treatment of overdose includes general supportive measures and, if necessary, hemodialysis.
Adverse reactions
Based on a pooled analysis of placebo-controlled adjunctive clinical trials in 1308 patients with partial-onset seizures, 61.9% of patients randomized to lacosamide and 35.2% of patients randomized to placebo experienced at least 1 adverse reaction. The most common adverse reactions (≥ 10%) with lacosamide were dizziness, headache, nausea, and diplopia. They were usually mild to moderate in intensity. Some of these were dose-related and resolved with dose reduction. The frequency and severity of central nervous system and gastrointestinal adverse reactions generally decreased over time.
In clinical trials, the drug was discontinued due to adverse events in 12.2% of cases compared to 1.6% with placebo. The most common reason for discontinuation of lacosamide treatment was dizziness.
The frequency of CNS adverse reactions (such as dizziness) may increase after a loading dose.
The following adverse reactions have been identified during clinical trials and post-marketing surveillance of adverse reactions. The frequency of adverse reactions was assessed as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), unknown frequency (cannot be estimated from the available data). Within each grouping, adverse reactions are presented in order of decreasing incidence.
Immune system disorders: uncommon – drug hypersensitivity1; unknown frequency – drug reaction with eosinophilia and systemic symptoms (DRESS)1,2.
Nervous system disorders: very common - dizziness, headache; common - balance disorder, memory impairment, cognitive impairment, drowsiness, tremor, nystagmus, hypoesthesia, dysarthria, disturbance in attention, paresthesia; uncommon - syncope2, coordination disorder; frequency unknown - convulsions3.
Psychiatric disorders: common: depression, confusional state, insomnia1; uncommon: aggression, agitation1, euphoric mood1, psychotic disorder1, suicide attempt1, suicidal ideation, hallucinations1.
On the part of the organs of vision: very often - diplopia; often - blurred vision.
From the side of the organs of hearing and vestibular apparatus: often - vertigo, tinnitus.
Cardiac disorders: uncommon – atrioventricular block1,2, bradycardia1,2, atrial fibrillation1,2, atrial flutter1,2; frequency unknown – ventricular tachyarrhythmia1.
Gastrointestinal: very often - nausea; often - vomiting, constipation, flatulence, dyspepsia, dry mouth, diarrhea.
Hepatobiliary system: uncommon – abnormal liver function tests1, increased liver enzymes (> 2 × ULN)1.
Skin and subcutaneous tissue disorders: common: pruritus, rash1; uncommon: angioedema1, urticaria1; frequency unknown: Stevens-Johnson syndrome1, toxic epidermal necrolysis1.
Musculoskeletal and connective tissue disorders: often - muscle spasm.
General disorders: often - gait disturbance, asthenia, increased fatigue, irritability, feeling of intoxication.
Injuries, poisonings and complications of procedures: often – falls, skin cracks, contusions.
Notes:
1 adverse reactions reported in the post-marketing period;
2 see Description of selected adverse reactions;
3 reported in open-label studies.
Certain adverse reactions.
The use of lacosamide is accompanied by a dose-dependent prolongation of the PR interval. Adverse reactions associated with prolongation of this interval (atrioventricular block, syncope, bradycardia) are possible.
In additional clinical trials in patients with epilepsy, first-degree AV block was uncommon, occurring in 0.7% and 0.5% of patients treated with lacosamide 200 mg and 600 mg, respectively, and not observed with lacosamide 400 mg or placebo, and second-degree or higher AV block was not observed in patients treated with lacosamide. However, cases of second- and third-degree AV block associated with lacosamide treatment have been reported during post-marketing surveillance.
In clinical trials, loss of consciousness occurred infrequently and the incidence did not differ between patients with epilepsy (n = 944) treated with lacosamide (0.1%) and patients with epilepsy (n = 364) treated with placebo (0.3%).
Atrial fibrillation or flutter was not reported in short-term clinical trials; however, both events were observed in open-label epilepsy trials and during post-marketing surveillance.
Deviations from the norm of laboratory parameters.
Liver function tests were abnormal in placebo-controlled studies of lacosamide in adult patients with partial-onset seizures receiving 1 to 3 concomitant antiepileptic medicinal products. Elevations of ALT to ≥ 3 × ULN (upper limit of normal) occurred in 0.7% (7/935) of patients treated with lacosamide and 0% (0/356) of patients treated with placebo.
Multiorgan hypersensitivity reactions.
Multi-organ hypersensitivity reactions (also known as drug reaction with eosinophilia and multi-organ system symptoms, DRESS) have been reported in patients taking certain antiepileptic medicinal products. These reactions have varied in presentation but have typically been accompanied by fever and rash and have been associated with multi-organ system involvement. If a multi-organ hypersensitivity reaction is suspected, lacosamide should be discontinued.
Children.
The frequency, type and severity of adverse reactions in children aged 16 years and older are expected to be similar to those in adults. The safety of the drug in children under 16 years of age has not been studied. No data are available.
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after obtaining a marketing authorisation is very important. This allows for continuous monitoring of the benefit/risk balance of the drug. Healthcare professionals are asked to report suspected adverse reactions.
Expiration date
4 years.
Storage conditions
Store in the original packaging out of the reach of children. No special storage conditions required.
Packaging
14 tablets in a blister; 4 blisters in a cardboard pack.
Vacation category
According to the recipe.
Producer
Genepharm SA.
Location of the manufacturer and address of its place of business
18th km of Marathonos Ave, Pallini Attiki, 15351, Greece.
