Vimpat, 150 mg 56 pcs.

• Pharmacodynamics

  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 enhances the slow inactivation of potential-dependent sodium channels selectively, leading to stabilization of hyperexcitable neuronal membranes.

  Lacosamide prevented the development of seizures of partial and primary generalized epilepsy in most animal models and delayed the development of increased seizure alertness. In preclinical studies, lacosamide in interaction with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, topiramate or gabapentin showed synergistic additive anticonvulsant effects.

  Clinical efficacy and safety

  The efficacy of Vimpat^® as adjunctive therapy at recommended doses (200, 400 mg/day) has been proven in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. The efficacy of Vimpat^® at a dose of 600 mg/day has also been demonstrated in controlled, additional therapeutic studies, although efficacy was comparable to the 400 mg/day dose, but tolerability of this dose (600 mg/day) was worse because of CNS and GI side effects. Therefore, the use of 600 mg/day is not recommended. The maximum recommended dose is 400 mg/day. These studies involving 1308 patients with a history of partial seizures over a mean period of 23 years were designed to evaluate the efficacy and safety of lacosamide with concomitant administration of 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.

  There is currently insufficient data on the feasibility of withdrawing concomitant antiepileptic medications for the use of lacosamide monotherapy.

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

  Pharmacokinetics

  Intake

  The infusion solution. C_max is reached by the time the infusion is completed. Plasma concentrations of lacosamide increase in proportion to dose after IV (50-300 mg) administration.

  The film-coated tablets. Lacosamide is quickly and completely absorbed after oral administration. Bioavailability of lacosamide in tablets is approximately 100%. After oral administration, plasma concentration of lacosamide increases rapidly, T_max is 0.5-4 h. Food intake does not affect the rate and extent of absorption.

  Distribution

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

  Metabolism

  95% of lacosamide is excreted through the kidneys unchanged (about 40%) and as O-desmethylmetabolite (less than 30%). The polar fraction (presumably serine derivatives) is approximately 20% in the urine and only in small amounts (0-2%) detected in plasma. Other metabolites are detected in the urine in amounts of 0.5-2%.

  In vitro data show that formation of O-desmethylmetabolite occurs mainly under the action of CYP2C19, 2C9 and 3A4 cytochrome isoenzymes. When comparing the pharmacokinetics of lacosamide in extensive metabolizers (with a functional CYP2C19 cytochrome isoenzyme) and slow metabolizers (lacking a functional CYP2C19 cytochrome isoenzyme), no clinically significant difference in lacosamide excretion was observed. In addition, interaction studies with omeprazole (an inhibitor of the CYP2C19 isoenzyme) showed no clinically significant changes in plasma concentrations of lacosamide, indicating the low significance of this pathway.

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

  Lacosamide is excreted by renal excretion and biotransformation. After oral ingestion and intravenous administration of lacosamide labeled with the radioactive isotope, approximately 95% radioactivity was noted in the urine and less than 0.5% in the feces. The T_1/2 of unchanged lacosamide is approximately 13 h. Pharmacokinetic parameters are dose proportional, constant over time, and characterized by low individual variability. When lacosamide is administered 2 times daily, C_ss in plasma is reached within 3 days. Cumulation is accompanied by an increase in plasma concentrations of approximately 2-fold.

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

  Particular patient groups

  Gender. Clinical studies show that gender has no significant effect on plasma concentrations of lacosamide.

  Race. There are no clinically significant differences in the pharmacokinetics of lacosamide in Asian, Negroid and Caucasoid races.

  Renal dysfunction. The AUC is increased to approximately 30% in mild to moderate renal failure and up to 60% in severe and terminal renal failure requiring hemodialysis compared to healthy patients, while the C_max is unchanged. Lacosamide is removed from plasma by hemodialysis. During the 4 h of the hemodialysis procedure, the AUC decreases by approximately 50%. Therefore, an additional dose is recommended after the hemodialysis procedure. In patients with moderate to severe renal insufficiency, the excretion of O-desmethylmetabolite decreased several times. In patients with terminal renal failure in the absence of hemodialysis, levels were increased and continuously increased during the 24-hour follow-up. It is not fully understood whether reduced metabolite excretion in patients with terminal renal failure may result in a change in the number of side effects, but it has been confirmed that O-desmethylmetabolite has no pharmacological activity.

  Hepatic impairment. In patients with moderate hepatic impairment, increased plasma concentrations of lacosamide have been observed (increased AUC by approximately 50%). One of the reasons for the increased exposure was decreased renal function in the patients who participated in the studies. Reduced nonrenal clearance in study patients was estimated as a 20% increase in the AUC of lacosamide. In patients with severe hepatic impairment, pharmacokinetics has not been studied.

  Elderly patients. Four elderly patients over 75 years of age participated in the study. AUC was increased by “30% in men and 50% in women compared to younger patients. This was partially due to decreased body weight, 26% in men and 23% in women of normal body weight. In studies in older patients, renal clearance of lacosamide was slightly decreased.

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Indications

Seizures, Epilepsy

As part of the complex therapy of partial seizures, with or without secondary generalization, in patients with epilepsy aged 16 years and older.

Vimpat^® as an infusion solution is indicated when oral administration is temporarily not possible.

Active ingredient

Lacosamide

Composition

Associates:

Microcrystalline cellulose,

Hyprolose low substituted,

ProSolv HD 90 (microcrystalline cellulose, colloidal anhydrous silica),

crosspovidone,

Magnesium stearate,

Hyprolose.

Composition of the film coating:

Opadray II 85G27190 golden (polyvinyl alcohol, talc, macrogol 3350, soy lecithin, titanium dioxide (E171), iron oxide yellow dye (E172), iron oxide red dye (E172), black iron oxide dye (E172)), opadray YS-3-7413 transparent (macro-gol 400, macro-gol 8000, hypromellose 3 cp, hypromellose 6 cp, hypromellose 50 cp).

How to take, the dosage

For oral administration

The daily dose is divided into 2 doses in the morning and evening, regardless of the time of meals.

The recommended starting dose is 50 mg twice daily. After 1 week, the dose is increased to 100 mg 2 times daily. Taking into account efficacy and tolerability, the maintenance dose can be increased when tablets are taken to 150 mg 2 times/day in week 3, when syrup is taken by 50 mg 2 times/day each week, up to a maximum daily dose of 400 mg/day (200 mg 2 times/day) from week 4.

The withdrawal of Vimpat^® is recommended gradually, reducing the dose by 200 mg per week.

Intravenous infusion

Intravenous infusion is given for 15-60 minutes 2 times/day.

The recommended starting dose is 50 mg 2 times/day. After 1 week, the dose is increased to 100 mg 2 times/day. Taking into account efficacy and tolerability, the maintenance dose can be increased weekly by 50 mg 2 times/day up to a maximum daily dose of 400 mg (200 mg 2 times/day). It is recommended to stop Vimpat^® gradually (reducing the dose by 200 mg per week).

The solution can be given without additional dilution or diluted.

There is experience with infusion solution for up to 5 days. Oral administration should be started as soon as possible.

The treatment with Vimpat^® can be initiated either with oral tablets or intravenous infusion of an infusion solution.

If necessary, the tablets may be replaced by an IV infusion without re-titration of the dose and vice versa. The daily dose and frequency of administration (2 times/day) should not be changed.

In patients with mild to moderate renal impairment (CKR >30 ml/min) when administered orally and by IV administration, no dose adjustment is required. In patients with severe renal impairment (CKD ≤30 ml/min) the maximum dose is 300 mg/day. Lacosamide is eliminated from plasma during hemodialysis, the AUC is reduced by approximately 50% within 4 hours after the procedure. For patients on hemodialysis, it is recommended to administer an additional 50% of the single dose immediately after the end of the procedure. Treatment of patients with severe renal insufficiency should be performed with caution, because clinical experience of using the drug in such patients is small, and accumulation of a metabolite with no known pharmacological activity is possible. Dose titration should be performed with caution in all patients with impaired renal function.

In oral and intravenous administration to patients with mild to moderate hepatic impairment, no dose adjustment is required. Caution should be exercised when titrating the dose in these patients given that impaired liver function is often associated with impaired renal function. Pharmacokinetics of lacosamide in patients with severe hepatic impairment have not been studied.

In oral and intravenous administration in elderly patients, dosage reduction is not required. There is limited experience with lacosamide in elderly patients with epilepsy. In the elderly, the possibility of an age-related decrease in renal clearance and a consequent increase in plasma concentrations of lacosamide must be considered.

Interaction

The results of studies indicate a low probability of interaction of lacosamide with other drugs.

In preclinical studies, synergism or additive anticonvulsant effects were observed in combination with levetiracetam, carbamazepine, phenytoin, valproic acid, lamotrigine, topiramate, gabapentin.

Lacosamide should be used cautiously in combination with drugs that cause prolongation of the PR interval (e.g., carbamazepine, lamotrigine, pregabalin) and class I antiarrhythmic drugs. However, no additional PR interval prolongation has been noted in clinical studies in patients who simultaneously took lacosamide in combination with carbamazepine or lamotrigine.

Lacosamide is a cytochrome P450 (CYP2C19) substrate.

Powerful enzyme inducers, such as rifampicin or Hypericum perforatum, may cause a moderate decrease in the systemic concentration of lacosamide. Therefore, caution should be exercised when such drugs are prescribed or withdrawn.

Lacosamide at any therapeutic dose has no effect on the C_ss in plasma of anticonvulsants, including levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine, phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam and zonisamide.

Carbamazepine and valproic acid had no effect on the plasma concentration of lacosamide.

Companion therapy with anticonvulsant enzyme-inducing agents (carbamazepine, phenytoin, phenobarbital in various doses) reduced total systemic exposure to lacosamide by 25%.

There is no evidence of significant interaction between lacosamide and the oral contraceptives ethinylestradiol and levonorgestrel. Lakosamide has no effect on progesterone concentrations.

Lacosamide has no effect on the pharmacokinetics of digoxin.

There are no clinically significant interactions between lacosamide and metformin.

There are no data on interaction of lacosamide with ethanol.

Omeprazole at a dose of 40 mg once daily increased AUC of lacosamide by 19%. This effect may not be clinically relevant. When administered as a single dose, lacosamide had no effect on the pharmacokinetics of omeprazole. The effect of other cytochrome P450 isoenzymes and other enzymes on the metabolism of lacosamide has not been accurately determined. Lacosamide is not a substrate or inhibitor of P-glycoprotein.

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

Special Instructions

Lacosamide treatment may be accompanied by dizziness, potentially leading to injuries and falls. Because of this, patients should use caution.

A review of data from clinical trials of anticonvulsant drugs suggests a slight increase in the risk of suicidal ideation and suicidal behavior. The mechanism of the increased risk is not clear; the existing data do not allow us to deny the existence of such a risk when taking lacosamide. Caregivers should be advised of the risk and the need to consult a specialist if suicidal behavior occurs. Patients treated with lacosamide should be closely monitored and warned to consult a specialist if suicidal ideation occurs.

With the possibility of prolongation of PR interval during therapy with Vimpat^®, periodic ECG monitoring is recommended for patients.

The syrup contains the excipients sodium propylparahydroxybenzoate (E217) and sodium methylparahydroxybenzoate (E219), which may cause allergic reactions (including delayed type). The syrup contains 3.7 g sorbitol (E420) per 200 mg of lacosamide, which corresponds to 9.7 kcal. The syrup contains 1.06 mmol (or 25.2 mg) of sodium per 200 mg of lacosamide. This should be considered if the patient is on a sodium-restricted diet.

Pediatric use

Lacosamide is not recommended for children and adolescents under the age of 16 years because the safety and effectiveness of the drug in these age groups has not been studied.

Impact on ability to drive and operate machinery

The drug may affect the ability to drive or operate complex machinery. Treatment with this drug may be accompanied by the development of dizziness or blurred vision. Accordingly, patients are not recommended to drive a car or operate complex machinery.

Contraindications

• V-blockade of degree II or III
• Age under 16 years
• Hereditary intolerance to fructose, sucrose-isomaltase deficiency, glucose-galactose malabsorption (because the syrup contains fructose
• phenylketonuria (because the syrup contains aspartame).
• phenylketonuria (because the syrup contains aspartame);
• high sensitivity to the ingredients of the drug, including soy (it contains aspartame).

Patients with severe renal insufficiency (CK≤30 ml/min), with conduction disorders, heart failure and previous history of myocardial infarction should be treated with caution. Particular caution should be observed in elderly patients with increased risk of heart disease, as well as when using lacosamide in combination with drugs that cause prolongation of PR interval.

Performance with hepatic impairment

There is no need for dose adjustment when administered orally and when administered intravenously in patients with mild to moderate hepatic impairment. Dose adjustments should be made with caution in these patients given that impaired liver function is often associated with impaired renal function. Pharmacokinetics of lacosamide in patients with severe hepatic impairment has not been studied.

Performance in renal impairment

In oral and intravenous administration in patients with mild to moderate renal impairment (KC >30 ml/min), no dose adjustment is required. In patients with severe renal impairment (CKD >30 ml/min), dosage adjustment is not required.

Side effects

In treatment with lacosamide, the most common adverse reactions were dizziness, headache, nausea, and diplopia. As a rule, they were mild to moderate in severity. The severity of some adverse reactions depended on the dose and decreased after its reduction. The frequency and severity of CNS and digestive system adverse reactions usually decreased with time.

Lacosamide use is accompanied by a dose-dependent prolongation of the PR interval, due to which clinical conditions such as AV blockade, syncope and bradycardia may develop.

The adverse reactions reported in more than 1% of patients in clinical trials are listed below. Determine the frequency of adverse reactions: very common (≥1/10); common (≥1/100 to

CNS side effects: very common – dizziness, headache; common – depression, irritability, balance disorder, movement coordination disorders, memory impairment, attention disorders, cognitive disorders, hypoesthesia, somnolence, confusion, tremor, nystagmus, dysarthria.

Sensory organs: very common – diplopia; common – blurred vision, vertigo, tinnitus.

The digestive system: very common – nausea; common – vomiting, constipation, flatulence, dyspepsia, dry mouth.

Dermatological reactions: often – itching.

Muscular system: often – muscle cramps.

Others: often – impaired gait, asthenia, fatigue, falls, increased risk of injury (due to impaired coordination and dizziness).

Overdose

Clinical data on lacosamide overdose are limited.

Symptoms: after taking the drug at a dose of 1200 mg/day – mainly dizziness and nausea, which disappeared after reducing the dose. During clinical trials, a single dose of 12 g of lacosamide was reported, which was taken together with toxic doses of other antiepileptic drugs. The patient became comatose, but then fully recovered without sequelae.

Treatment: there is no antidote for lacosamide; symptomatic therapy is given; hemodialysis may be used if necessary.

Pregnancy use

There are no clinical data on the use of lacosamide in pregnancy. Lacosamide should not be used in pregnancy unless the benefit to the mother clearly outweighs the possible risk to the fetus.

If a woman is planning to become pregnant, the appropriateness of using the drug should be carefully weighed.

There have been no teratogenic effects in experimental studies, but embryotoxicity has been noted with high (toxic) doses.

There are no data on excretion of lacosamide with human breast milk. Excretion of lacosamide with breast milk has been noted in experimental studies.

Breastfeeding should be stopped during treatment with lacosamide.

Pediatric use

It is contraindicated in children and adolescents under 16 years of age.

Vimpat is contraindicated in children under 16 years of age, pregnant women and during lactation.