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Pharmacological properties

The exact mechanism of antiepileptic action of lacosamide has not been established. The following observations may be relevant to explain the therapeutic effect of the drug. in electrophysiological studies in vitro it was found that lacosamide selectively enhances the slow inactivation of voltage-dependent sodium channels, which leads to stabilization of hyper-excitable neuronal membranes. in addition, lacosamide binds to the crmp-2 phosphoprotein, which is expressed primarily in the nervous system and is involved in the regulation of neuronal differentiation and axon growth.

Pharmacodynamics The anticonvulsant efficacy of lacosamide has been established in different experiments on animals with partial and primary generalized seizures and a delay in the development of kindling (epileptogenesis of experimental animals). In preclinical studies, lacosamide showed a synergistic or additive anticonvulsant effect in combination with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, Topiramate or gabapentin.

There is insufficient data on the effectiveness of lacosamide monotherapy.

Clinical experience

The effectiveness of Vimpat as an adjunctive therapy at recommended doses (200 and 400 mg / day) was established in three multicenter, randomized, placebo-controlled clinical trials lasting 12 weeks. The effectiveness of the drug 600 mg / day was also established during controlled trials of additional therapy, although the effectiveness of this dose was the same as 400 mg / day. At the same time, patients tolerated a lower dose better, since when using 600 mg / day, adverse reactions from the central nervous system and gastrointestinal tract occurred. Thus, it is not recommended to prescribe a dose of 600 mg / day. The maximum recommended dose is 400 mg / day. The purpose of these studies, in which 1308 patients participated, with a history of an average of 23 years of partial seizures, was to evaluate the efficacy and safety of lacosamide when used simultaneously with 1-3 other antiepileptic drugs in individuals with uncontrolled partial seizures as with secondary generalization, so without it. Overall, the number of patients with a 50% reduction in seizure frequency was 23; 34 and 40% with placebo, lacosamide 200 and 400 mg / day, respectively.

Pharmacokinetics Suction. Lacosamide is rapidly and completely absorbed after oral administration. The bioavailability of lacosamide in tablets is approximately 100%. After oral administration, the concentration of lacosamide in blood plasma rises rapidly, Cmax achieved after 0.5–4 hours. Tablets and syrup for oral administration are bioequivalent. Food does not affect the rate and extent of absorption.

After iv administration of Cmax achieved at the end of the infusion. The concentration in the blood plasma increases in proportion to the dose after oral administration (100-800 mg) and iv administration (50-300 mg).

Distribution. The distribution volume is approximately 0.6 l / kg body weight, the degree of binding to plasma proteins is 15%.

Metabolism. 95% of the dose is excreted by the kidneys unchanged (≈40% of the dose) and in the form of metabolites (O-desmethyl metabolite - 30%). The proportion of the polar fraction in the urine (probably serine derivatives) was ≈20%, however, it was detected in the blood plasma only in a small amount (0–2%) in some patients. The amount of other metabolites detected in urine is 0.5–2%.

The formation of O-desmethyl metabolite occurs mainly under the influence of CYP 2C19. Other enzymes involved in the metabolism of lacosamide have not been established. However, no clinically significant differences were observed between the effects of lacosamide when comparing its pharmacokinetics with strong metabolizers (EM, with functioning CYP 2C19) and weak metabolizers (PM, with insufficient functioning of CYP 2C19).

In addition, a study of the interaction with omeprazole (a CYP 2C19 inhibitor) showed the absence of clinically significant changes in the concentration of lacosamide in blood plasma, which indicates the insignificant significance of this pathway. No other enzymes involved in the metabolism of lacosamide have been identified. The concentration of O-desmethyl metabolite in blood plasma is approximately 15% of the concentration of lacosamide. This metabolite does not have pharmacological activity.

Lacosamide is excreted by renal excretion and biotransformation. After oral administration of radioactively labeled lacosamide, ≈95% of the radioactivity was detected in urine and 0.5% in feces. T½ is ≈13 hours. Pharmacokinetics is proportional to the dose, does not change with time and is characterized by low inter- and intraindividual variability. When applied 2 times a day, equilibrium plasma concentrations are reached within 3 days. Cumulation is accompanied by an increase in plasma concentration by approximately 2 times.

Pharmacokinetics in special patient groups

Floor. Clinical studies have shown that gender does not have a clinically significant effect on the concentration of lacosamide in blood plasma.

Impaired renal function. The AUC value for lacosamide increased by approximately 30% in patients with mild and moderate renal impairment and by 60% in individuals with severe renal impairment and in patients with end-stage renal disease who require hemodialysis. However, these diseases do not affect Cmax.

Lacosamide is effectively removed from blood plasma during hemodialysis. After 4 hours of hemodialysis, the AUC of lacosamide is reduced by ≈50%. Therefore, after hemodialysis, it is recommended to increase the dose of the drug. The effect of O-desmethyl metabolite increases several times in patients with moderate and severe renal impairment. If hemodialysis was not performed in patients with end-stage renal failure, these values ​​increased continuously, as can be seen from analyzes performed over 24 hours. It is not known whether an increase in the effect of the drug metabolite in patients with end-stage renal failure can cause adverse reactions, but not revealed no pharmacological activity of this metabolite.

Impaired liver function. In patients with moderate liver dysfunction (class B on the Child-Pugh scale), an increase in the concentration of lacosamide was detected (≈50% higher than AUCnorm) The increased effect of the drug is partially due to a decrease in renal function in study participants. A decrease in non-renal clearance in patients participating in the study caused an increase in AUC of lacosamide by 20%. The pharmacokinetics of lacosamide in individuals with severely impaired liver function has not been studied.

Persons of advanced age (over 65 years old). In studies conducted with the participation of elderly women and men and included 4 patients over the age of 75 years, the AUC level of ≈30 and ≈50% was higher compared to young people, respectively. This result is partially caused by underweight. This difference is 26 and 23%, respectively, with the reduced difference in body weight. An increase in the variability of the effect of the drug on the patient was also noted. In the course of this study, it was found that in the elderly, the renal clearance of lacosamide was slightly reduced.

The total dose of the drug should be reduced only in case of decreased renal function.

Indications

Vimpat is used to treat partial seizures that are accompanied or not accompanied by secondary generalization in patients with epilepsy over the age of 16 years as part of complex therapy.

Application

Vimpat in the form of a solution for infusion is used as an alternative treatment in patients who are temporarily unable to take the drug orally.

The use of the drug in / 2 times a day for no more than 5 days is recommended. Vimpat is used iv twice a day. The solution is administered iv for 15-60 minutes 2 times a day. RR can be administered without further dilution. If necessary, you can switch from taking the drug orally to iv administration without dose titration and vice versa. In this case, the daily dose and frequency of administration (2 times a day) should not be changed. Vimpat in the form of tablets and syrup is used orally 2 times a day. The recommended starting dose is 50 mg 2 times a day. After 1 week, the dose is increased to 100 mg 2 times a day. Given the effectiveness and tolerability, the maintenance dose can be increased every week by 50 mg 2 times a day to a maximum daily dose of 400 mg / day (200 mg 2 times a day). Tablets or syrup can be taken without regard to meals.

Cancel Vimpat is recommended gradually (reducing the dose by 200 mg / week).

Use in patients with impaired renal function. For patients with mild to moderate impaired renal function (creatinine clearance 30 ml / min), dose adjustment is not required. In patients with severe renal failure (creatinine clearance ≤30 ml / min) and terminal kidney disease, the maximum dose is 250 mg / day. Hemodialysis patients are advised to add an additional 50% of the distributed daily dose immediately at the end of the procedure. Treatment of patients with terminal kidney disease should be carried out carefully, since the clinical experience of using the drug in such patients is small and the accumulation of a metabolite that does not have pharmacological activity is possible. All patients with impaired renal function are advised to carefully dose titration.

Use in patients with impaired liver function. Patients with mild to moderate impaired liver function do not require dose adjustment. The dose should be titrated in such patients carefully, given the possibility of concomitant renal impairment. The pharmacokinetics of lacosamide has not been studied in individuals with severe hepatic impairment.

Use in elderly patients (over 65 years old). For elderly patients, there is no need to reduce the dose. Experience with lacosamide in the elderly with epilepsy is limited. In elderly patients, it is necessary to consider the possibility of an age-related decrease in renal clearance and an increase in AUC.

Use in children. Vimpat is not recommended for children and adolescents under the age of 16 years, since the safety and effectiveness of the drug in these age groups have not been studied.

Contraindications

Hypersensitivity to the active substance, peanuts, soy or other excipients. atrioventricular block of the II or III degree.

Side effects

Based on an analysis of the generalized results of placebo-controlled clinical trials in which 1308 patients with partial seizures participated, it was found that 61.9% of patients randomized to the lacosamide group and 35.2% of patients randomized to the placebo group had at least at least 1 adverse reaction. the most common adverse reactions were dizziness, headache, nausea, and diplopia. side effects of the drug were most often mild or moderate. the occurrence of some of them was dose-dependent, and a decrease in the dose of the drug led to a decrease in the severity of side effects. the frequency and severity of adverse reactions from the central nervous system and gastrointestinal tract decreased after some time.

The use of the drug in clinical trials with the occurrence of side effects was discontinued in 12.2% of cases compared with 1.6% with placebo. The most common cause of discontinuation of lacosamide treatment was dizziness.

The use of lacosamide is accompanied by a dose-dependent extension of the PR interval. Undesirable reactions associated with lengthening of this interval (AV block, fainting, bradycardia) are possible.

In patients with epilepsy, grade I AV blockade is infrequent, 0.7; 0; 0.5 and 0% at a dose of lacosamide 200; 400; 600 mg and placebo, respectively. In patients taking lacosamide, AV block II or higher was not observed.

Loss of consciousness occurred infrequently. Moreover, the incidence is almost the same in patients receiving lacosamide (0.1%), and in individuals who received placebo (0.3%).

The following are adverse reactions identified during the analysis of the generalized results of placebo-controlled clinical trials. The frequency of adverse reactions was estimated as follows: very often (≥1 / 10), often (≥1 / 100 to 1/10), infrequently (≥1 / 1000 to 1/100). In each group, adverse reactions are listed in decreasing order of severity.

From the side of the central nervous system: very often - dizziness, headache; often - imbalance, impaired coordination, impaired memory, cognitive impairment, drowsiness, tremor, nystagmus.

Mental disorders: often - depression.

From the side of the organ of vision: very often - diplopia; often - blurred vision.

On the part of the organ of hearing and the vestibular apparatus: often - vertigo.

From the gastrointestinal tract: very often - nausea; often - vomiting, constipation, flatulence.

On the part of the skin and subcutaneous tissue: often - itching.

General disorders: often - gait disturbance, asthenia, fatigue.

Injuries, poisoning and complications of the procedures: often - falls, skin cracks.

special instructions

Lacosamide treatment is sometimes accompanied by dizziness, which can lead to an increase in the frequency of accidental damage and falls. therefore, patients should be warned about the possible effects of the drug and recommended caution.

In clinical studies, a prolongation of the P – R interval was observed while taking lacosamide. Lacosamide should be used with caution in patients with known cardiac conduction disorders or serious heart diseases, namely, myocardial infarction or a history of heart failure. With extreme caution, the drug is used in the elderly, since they may be at increased risk of heart disease, or when lacosamide is used simultaneously with drugs that cause a prolongation of the P – R interval.

Suicidal thinking and behavior have been observed in patients receiving antiepileptic drugs for various diseases. A meta-analysis of randomized, placebo-controlled clinical trials of anticonvulsants also showed a slight increase in the risk of suicidal ideation and behavior. The mechanism of this risk is unknown, and the available data do not exclude the possibility of increasing the risk with the use of lacosamide.

Thus, it is necessary to control the occurrence of signs of suicidal thinking and behavior in patients and prescribe, if necessary, appropriate treatment. It is recommended that patients and persons who monitor them should consult a doctor if signs of suicidal thinking and behavior occur.

The syrup contains sodium propylhydroxybenzoate (E217) and sodium methylhydroxybenzoate (E219), which can cause allergic reactions (possibly delayed type). 1 dose of the drug (200 mg of lacosamide) contains 3.7 g of sorbitol (E420), which is 9.7 kcal. Patients with a rare disease - congenital fructose intolerance should not take this drug. The composition of the syrup also includes aspartame (E951) - a source of phenylalanine, which can be harmful to patients with phenylketonuria. 1 dose of syrup (200 mg of lacosamide) contains 1.06 mmol (or 25.2 mg) of sodium. This must be considered when used in patients who are on a diet with a limited intake of salt.

1 bottle of the drug in the form of a solution for infusion contains 2.6 mmol (or 59.8 mg) of sodium.This must be considered when used in patients who are on a diet with a limited intake of salt.

Use during pregnancy and lactation

Pregnancy

The risk associated with epilepsy and the use of antiepileptic drugs in general: in newborns in women with epilepsy, the frequency of congenital malformations is 2-3 times higher than in the general population (≈3%). Combination antiepileptic therapy in pregnant women was accompanied by an increase in the frequency of congenital malformations in children, but it remains unclear to what extent this is associated with treatment and / or the disease itself. Moreover, effective antiepileptic therapy should not be interrupted during pregnancy, since worsening of the disease can have serious consequences for both the mother and the fetus.

Risk associated with the use of lacosamide: there is no relevant data regarding the use of lacosamide in pregnant women. In studies in animals (rats and rabbits), the teratogenic effects of the drug were not detected, but embryotoxicity was noted when the drug was administered in doses toxic to the mothers body. The possible risk to pregnant women is unknown. Lacosamide should not be used in pregnant women, unless treatment is necessary (if the benefit to the mother clearly outweighs the possible risk to the fetus). If a woman is planning a pregnancy, then it is necessary to carefully weigh the appropriateness of using this drug.

Lactation

There is no data on the excretion of lacosamide with breast milk. Animal studies have confirmed that lacosamide passes into milk. As a caution, breast-feeding should be discontinued during treatment with lacosamide.

Children. Use the drug in children under the age of 16 years is not recommended.

The ability to influence the reaction rate when driving vehicles and working with mechanisms. Vimpat can slightly or moderately affect the ability to drive vehicles and work with mechanisms. Treatment with the drug may be accompanied by the development of dizziness or blurred vision. Accordingly, patients are not recommended to drive vehicles or work with sophisticated equipment until the response to Vimpat has been evaluated.

Interactions

Lacosamide should be used with caution in combination with drugs that cause a prolongation of the pr interval (e.g. carbamazepine, lamotrigine, pregabalin) and class I antiarrhythmic drugs. however, in clinical studies, there was no additional lengthening of the pr interval in patients simultaneously taking lacosamide in combination with carbamazepine or lamotrigine.

Research results indicate a low reliability of the interaction of lacosamide with other drugs. In vitro studies have shown that lacosamide does not induce CYP 1A2, 2B6 and 2C9 enzymes and does not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6 and 2E1 at such plasma concentrations as were used in clinical trials. In vitro studies have shown that lacosamide is not transported by intestinal P-glycoprotein. In vivo, lacosamide does not inhibit or induce the CYP 2C19 enzyme.

In vitro data showed that lacosamide may be a weak inhibitor and inducer of CYP 3A4. The clinical significance of this effect is unknown. When studying the interaction with carbamazepine, there were no signs of a pronounced inhibitory effect of lacosamide in therapeutic doses on the metabolism catalyzed by CYP 3A4.

Powerful enzyme inducers, such as rifampicin or St. Johns wort (Hypericum perforatum), can cause a moderate decrease in the systemic concentration of lacosamide. In this regard, with the appointment of such drugs or their cancellation, care must be taken.

Antiepileptic drugs

Lacosamide did not cause significant changes in plasma concentrations of carbamazepine and valproic acid.In turn, carbamazepine and valproic acid did not affect the level of lacosamide in blood plasma. According to the pharmacokinetic analysis of the population, concomitant therapy with other antiepileptic drugs that induce enzymes (carbamazepine, phenytoin, phenobarbital in different doses) reduced the total systemic exposure of lacosamide by 25%.

Oral contraceptives

No evidence of significant interaction between lacosamide and oral contraceptives, ethinyl estradiol and levonorgestrel. Lacosamide did not affect progesterone concentrations.

Other

Lacosamide did not affect the pharmacokinetics of digoxin. No clinically significant interaction of lacosamide and metformin was detected. Omeprazole at a dose of 40 mg once a day increased the AUC of lacosamide by 19%. This effect probably has no clinical significance. When taking a single dose, lacosamide did not affect the pharmacokinetics of omeprazole. There is no data on the interaction of lacosamide with alcohol. The degree of binding of lacosamide to plasma proteins is 15%. In this regard, a clinically significant interaction with other drugs that bind to proteins is unlikely.

Incompatibility. It was found that the Vimpat drug in the form of a solution for infusion when mixed with the following solvents is physically compatible and chemically stable for at least 24 hours if it is in glass or PVC containers at a temperature of no higher than 25 ° C.

Solvents:

  • sodium chloride 9 mg / ml (0.9%), injection solution;
  • glucose 50 mg / ml (5%), injection solution;
  • Ringers lactate injection.

From a microbiological point of view, the drug should be used immediately. If it is not used immediately, then the user is responsible for the time and storage conditions and usually they cannot be more than 24 hours at a temperature of 2–8 ° C, unless dilution is carried out under controlled and approved aseptic conditions.

Overdose

Clinical evidence of an overdose of lacosamide is limited. after taking the drug at a dose of 1200 mg / day, clinical symptoms (dizziness and nausea) were mainly associated with central nervous system and gastrointestinal tract and disappeared after a dose reduction. the highest dose of an overdose that was reported during the clinical development program was taking 12 g of the drug simultaneously with several other antiepileptic drugs in toxic doses (the patient was in a coma; over time, his condition completely recovered without persistent complications).

There is no antidote for lacosamide. Overdose treatment includes general supportive measures and, if necessary, hemodialysis.

Storage conditions

In a dry, dark place at a temperature of no higher than 30 ° C, the solution for infusion is at a temperature of no higher than 25 ° C. after the first opening of the vial, use the syrup for 4 weeks.

Tags: Vimpat® [Lacosamide]