Vimpat, pills 100mg, 14pcs

Composition

Auxiliary substances:

microcrystalline cellulose,

low-substituted giprolose,

prosolv HD 90 (microcrystalline cellulose, colloidal anhydrous silicon dioxide),

crospovidone,

magnesium stearate,

giprolose.

Composition of the film shell:

opadray II 85G32445 yellow (polyvinyl alcohol, talc, macrogol 3350, soy lecithin, titanium dioxide (E 171),

iron oxide yellow dye (E 172)),

opadray YS-3-7413 transparent (macrogol 400, macrogol 8000, hypromellose 3 cp, hypromellose 6 cp, hypromellose 50 cp).

Pharmacological action

Pharmacodynamics

The Active ingredient lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalized amino acid.

The exact mechanism of antiepileptic action of lacosamide has not been established. In vitro electrophysiological studies, lacosamide increases the slow inactivation of potential-dependent sodium channels selectively, which leads to the stabilization of hyperexcitable neuronal membranes.

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

Clinical efficacy and safety

The effectiveness of Vimpat® as an adjunct therapy at the recommended doses (200,400 mg / day) was proven in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. The effectiveness of Vimpat® at a dose of 600 mg / day was also shown in controlled additional therapeutic studies, although the effectiveness was comparable to a dose of 400 mg / day, but the tolerability of this dose (600 mg / day) was worse due to side effects from the central nervous system and gastrointestinal tract. Therefore, the use of a dose of 600 mg / day is not recommended. The maximum recommended dose is 400 mg / day. These studies, involving 1,308 patients with a history of partial seizures over a mean period of 23 years, were designed to evaluate the efficacy and safety of lacosamide in concomitant use 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.

Currently, there is insufficient data on the possibility of discontinuing concomitant antiepileptic drugs for the use of lacosamide monotherapy.

Pharmacokinetics and safety of a single saturating dose infusion lacosamide was determined in a multicenter open study of the safety and tolerability of rapid initiation of therapy lacosamide using a single/in a saturating dose (200 mg), with subsequent oral use of the drug 2 times / day (dose equivalent to/dose) as adjunctive therapy in adult patients 16 to 60 years of age with partial seizures.

Pharmacokinetics

Suction

Solution for infusions. Cmax is reached by the end of the infusion. The concentration of lacosamide in plasma increases proportionally to the dose after intravenous (50-300 mg) use.

Film-coated tablets. Lacosamide is rapidly and completely absorbed after oral use. The bioavailability of lacosamide in tablets is approximately 100%. After oral use, the concentration of lacosamide in plasma increases rapidly, T_max-0.5-4 hours. Food intake does not affect the rate and degree of absorption.

The distribution_of Vd is approximately 0.6 l / kg, and the degree of binding to plasma proteins is less than 15%.

Metabolism

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

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

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

Deduction

Lacosamide is eliminated by renal excretion and biotransformation. After oral use and intravenous use of lacosamide labeled with a radioactive isotope, about 95% of radioactivity was detected in the urine and less than 0.5% in the feces. T_1/2 of unchanged lacosamide is approximately 13 h. Pharmacokinetic parameters are dose-proportional, constant over time, and characterized by low individual variability. With the use of lacosamide 2 times a day, C_ss in plasma is reached within 3 days. Cumulation is accompanied by a 2-fold increase in plasma concentrations.

C_ss with a single loading dose of 200 mg is comparable to that with oral use of 100 mg 2 times a day.

Special patient groups

Gender. Clinical studies show that gender does not significantly affect the concentration of lacosamide in blood plasma.

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

Impaired renal function. The AUC value increases to approximately 30% in mild to moderate renal insufficiency and up to 60% in severe and end-stage renal insufficiency requiring hemodialysis, compared with healthy patients, while the_cmax does not change. Lacosamide is removed from the plasma by hemodialysis. During the 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 insufficiency, the excretion of O-desmethylmetabolite decreased several times. In patients with end-stage 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 excretion of the metabolite in patients with end-stage renal failure can lead to a change in the number of side effects, but it was confirmed that O-desmethylmetabolite does not have pharmacological activity.

Impaired liver function. In patients with moderate hepatic insufficiency, increased plasma concentrations of lacosamide were observed (an increase in AUC by approximately 50%). One of the reasons for increased exposure was reduced renal function in patients who participated in the study. The decrease in non-renal clearance in patients from the study was estimated as a 20% increase in the AUC of lacosamide. Pharmacokinetics have not been studied in patients with severe hepatic insufficiency.

Elderly patients. The study involved 4 elderly patients over 75 years of age. AUC was increased by “30% in men and 50% in women compared to younger patients. This is partly due to reduced body weight,26% in men and 23% in women of normal body weight. In studies in elderly patients, the renal clearance of lacosamide was slightly reduced.

Indications

As part of the complex therapy of partial convulsive seizures, accompanied or not accompanied by secondary generalization, in patients with epilepsy aged 16 years and older.

Vimpat® in the form of an infusion solution is prescribed in cases where it is temporarily impossible to take the drug orally.

Use during pregnancy and lactation

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

If a woman is planning pregnancy, then it is necessary to carefully weigh the feasibility of using this drug.

In experimental studies, no teratogenic effects were recorded, but embryotoxicity was noted when used in high (toxic) doses.

There are no data on the excretion of lacosamide in human breast milk. Lacosamide excretion in breast milk has been reported in experimental studies.

Breast-feeding should be discontinued during lacosamide treatment.

Use in children

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

Contraindications

• AV-block II and III degree;
• the age of 16;
• hereditary fructose intolerance, sucrase deficiency-isomaltase, glucose-galactose malabsorption (as in the composition of the syrup contains fructose);
• phenylketonuria (as in the composition of the syrup contains aspartame);
• hypersensitivity to the components of the drug, including soy (part of shell tablet), as well as peanuts.

The drug should be used with caution in patients with severe renal insufficiency (creatinine clearance < 30 ml/min), with conduction disorders, heart failure and a history of myocardial infarction. Special care should be taken in elderly patients who have an increased risk of heart disease, as well as when using lacosamide in combination with drugs that cause prolongation of the PR interval.

Use in patients with liver function disorders

No dose adjustment is required for oral or intravenous use in patients with mild to moderate hepatic impairment. Titrate the dose to such patients with caution, given that impaired liver function is often accompanied by impaired renal function. The pharmacokinetics of lacosamide in patients with severe hepatic insufficiency have not been studied.

Use in patients with impaired renal function

No dose adjustment is required when administered orally or intravenously in patients with mild to moderate renal impairment (creatinine clearance >30 ml/min). In patients with severe renal insufficiency (CC

Side effects

When treated with lacosamide, the most common adverse reactions were dizziness, headache, nausea, and diplopia. As a rule, they were mild or moderate. The severity of some adverse reactions depended on the dose and decreased after its reduction. The frequency and severity of adverse reactions from the central nervous system and digestive system usually decreased over time.

The use of lacosamide is accompanied by a dose-dependent prolongation of the PR interval, which may lead to the development of such clinical conditions as AV block, syncope and bradycardia.

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

From the central nervous system: very often – dizziness, headache; often-depression, irritability, balance disorders, impaired coordination of movements, memory disorders, attention disorders, cognitive disorders, hypesthesia, drowsiness, confusion, tremor, nystagmus, dysarthria.

From the side of the senses: very often – diplopia; often-blurred vision, vertigo, tinnitus.

From the digestive system: very often – nausea; often-vomiting, constipation, flatulence, dyspepsia, dry mouth.

Dermatological reactions: often – itching.

Musculoskeletal disorders: often-muscle spasms.

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

Interaction

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

In preclinical studies, a synergistic or additive anticonvulsant effect was 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 (for example, carbamazepine, lamotrigine, pregabalin) and Class I antiarrhythmic drugs. However, in clinical studies, no additional prolongation of the PR interval was observed 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, can cause a moderate decrease in the systemic concentration of lacosamide. In this regard, caution should be exercised when prescribing such drugs or canceling them.

Levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine, phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide do not affect the plasma CV of anticonvulsants at any therapeutic dose.

Carbamazepine and valproic acid did not affect the concentration of lacosamide in plasma.

Concomitant therapy with anticonvulsants that induce enzymes (carbamazepine, phenytoin, phenobarbital in various doses) reduced the total systemic exposure of lacosamide by 25%.

There were no signs of a significant interaction between lacosamide and the oral contraceptives ethinyl estradiol and levonorgestrel. Lacosamide does not affect the concentration of progesterone.

Lacosamide does not affect the pharmacokinetics of digoxin.

There was no clinically significant interaction between lacosamide and metformin.

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

Omeprazole at a dose of 40 mg 1 time / day increased the AUC of lacosamide by 19%. This effect may not be clinically relevant. Lacosamide did not affect the pharmacokinetics of omeprazole in a single dose. The effect of other cytochrome P 450 isoenzymes and other enzymes on lacosamide metabolism has not been precisely established. Lacosamide is not a substrate or inhibitor of P-glycoprotein.

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

How to take, course of use and dosage

For oral use

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

The recommended starting dose is 50 mg twice daily. After 1 week, the dose is increased to 100 mg 2 times / day. Taking into account the effectiveness and tolerability, the maintenance dose can be increased when taking tablets, it can be increased to 150 mg 2 times/day in the third week of use, when taking syrup-by 50 mg 2 times / day every week, up to a maximum daily dose of 400 mg/day (200 mg 2 times/day) from the fourth week.

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

For intravenous use

IV is administered for 15-60 minutes 2 times / day.

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

The solution can be administered without additional dilution or diluted.

There is experience in using a solution for infusions lasting up to 5 days. You should switch to taking the drug inside as soon as it becomes possible.

Treatment with Vimpat® can be initiated either with oral tablets or with intravenous use of an infusion solution.

If necessary, you can replace the tablets with intravenous use without re-titrating the dose and vice versa. At the same time, you should not change the daily dose and frequency of use (2 times/day).

Oral and intravenous use in patients with mild to moderate renal impairment (creatinine clearance >30 ml / min) no dose adjustment is required. Patients with severe renal insufficiency (creatinine clearance <30 ml / min)the maximum dose is 300 mg / day. Lacosamide is removed from the plasma by hemodialysis, and within 4 hours after the procedure, the AUC decreases by approximately 50%. Patients undergoing hemodialysis are recommended to receive an additional 50% of a single dose immediately after the end of the procedure. Treatment of patients with severe renal insufficiency should be carried out with caution, since the clinical experience of using the drug in such patients is small, and accumulation of a metabolite with no known pharmacological activity is possible. In all patients with impaired renal function, titration of the dose is recommended with caution.

No dose adjustment is required for oral or intravenous use in patients with mild to moderate hepatic impairment. Titrate the dose to such patients with caution, given that impaired liver function is often accompanied by impaired renal function. The pharmacokinetics of lacosamide in patients with severe hepatic insufficiency have not been studied.

When taken orally and when administered intravenously to elderly patients, no dose reduction is required. Experience with lacosamide in elderly patients with epilepsy is limited. In the elderly, it is necessary to consider the possibility of an age-related decrease in renal clearance and, as a result, an increase in the concentration of lacosamide in blood plasma.

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 recorded, which was taken together with toxic doses of other antiepileptic drugs. The patient fell into a comatose state, but then fully recovered without consequences.

Treatment: there is no antidote to lacosamide; symptomatic therapy is performed; if necessary, hemodialysis may be used.

Special instructions

Lacosamide treatment may be accompanied by dizziness, potentially leading to injuries and falls. In this regard, patients should exercise caution.

Analysis of data from clinical trials of anticonvulsants indicates a small increase in the risk of suicidal thoughts and suicidal behavior. The mechanism of increased risk is not clear, and existing data do not allow us to deny the existence of such a risk when taking lacosamide. Caregivers should be warned about the risk involved and the need to consult a specialist in the event of suicidal behavior. Patients receiving lacosamide treatment should be closely monitored and advised to consult a specialist if suicidal thoughts occur.

Given the possibility of prolonging the PR interval during therapy with Vimpat®, patients are recommended to periodically monitor the ECG.

The syrup contains excipients sodium propyl parahydroxybenzoate (E 217) and sodium methyl parahydroxybenzoate (E 219), which can cause allergic reactions (including delayed type). The syrup contains 3.7 g of sorbitol (E 420) 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 taken into account if the patient follows a diet with limited sodium intake.

Use in pediatrics

Lacosamide is not recommended for use in children and adolescents under 16 years of age, as the safety and efficacy of the drug in these age groups have not been studied.

Influence on the ability to drive motor vehicles and manage mechanisms

The drug may affect the ability to drive a car or use complex equipment. 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 equipment.

Form of production

Film-coated tablets

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Lacosamide

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For children over 16 years of age, For adults as prescribed by a doctor, For Children as prescribed by a doctor

Indications

Epilepsy