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The active substance - lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalized amino acid.
The exact mechanism of the antiepileptic effect of lacosamide has not been established. In in vitro electrophysiological studies, lacosamide selectively enhances the slow inactivation of potential-dependent sodium channels, which leads to stabilization of the hyper-excitable neuronal membranes.
Lacosamide on a large number of animal models prevented the development of attacks 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, valproate, lamotrigine, topiramate or gabapentin demonstrated a synergistic additive anticonvulsant effect.
Clinical efficacy and safety
The effectiveness of the drug Vimpat®® as an additional therapy in 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 the drug Vimpat®® A dose of 600 mg / day was also shown during controlled additional therapeutic studies, although the effectiveness was comparable to the 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 1308 patients with data from the history of the development of partial seizures over an average period of 23 years were designed to evaluate the efficacy and safety of lacosamide with the concomitant administration of 1-3 anti-epileptic drugs in patients with uncontrolled partial seizures with or without secondary generalization. The overall proportion of patients with a 50% decrease in the incidence of seizures in the placebo, 200 mg / d and lacosamide groups and 400 mg / d was 23, 34 and 40%, respectively.
Currently, there is insufficient evidence on the possibility of discontinuation of concomitant antiepileptic drugs for use of lacosamide monotherapy.
The pharmacokinetics and safety of a single saturating dose of an infusion lacosamide was determined in a multicenter open study of the safety and tolerability of a quick start of lacosamide therapy using a single IV saturation dose (200 mg), followed by oral administration of the drug 2 times a day (at a dose equivalent to dose) as an additional therapy in adult patients from 16 to 60 years with partial attacks.
Solution for infusions. Cmax achieved by the end of the infusion. Plasma lacosamide concentration increases in proportion to the dose after iv administration (50-300 mg) of administration.
pills, film coated. Lakosamid quickly and completely absorbed after ingestion. The bioavailability of lacosamide pills is approximately 100%. After ingestion, plasma lacosamide concentration increases rapidly, Tmax - 0.5–4 hours. Eating does not affect the rate and extent of absorption.
Vd is about 0.6 l / kg, the degree of binding to plasma proteins is less than 15%.
95% of lacosamide is eliminated through the kidneys in unchanged form (about 40%) and as O-dezmetilmetabolita (less than 30%). The polar fraction (presumably, derivatives of serine) is approximately 20% in the urine and only in small quantities (0–2%) is found in the blood plasma. Other metabolites are determined in the urine in the amount of 0.5-2%.
In vitro data show that O-desmethylmetabolite is formed mainly under the action of cytochrome CYP2C19, 2C9, and 3A4 isoenzymes.When comparing the pharmacokinetics of lacosamide in extensive metabolisers (with the functional cytochrome CYP2C19 isoenzyme) and slow metabolizers (lacking the functional cytochrome isoenzyme CYP2C19), there was no clinically significant difference in the release of lacosamide. In addition, studies on interaction with omeprazole (an inhibitor of the isoenzyme CYP2C19) showed no clinically significant changes in plasma lacosamide concentrations, indicating a low significance of this pathway.
The concentration of O-desmethylmetabolite in plasma is approximately 15% of the concentration of lacosamide. This metabolite does not possess pharmacological activity.
Lacosamide is eliminated by renal excretion and biotransformation. After oral administration and intravenous administration of lacosamide, labeled with a radioactive isotope, about 95% of the radioactivity was observed in the urine and less than 0.5% in the feces. T1/2 unchanged lacosamide is about 13 hours. Pharmacokinetic parameters are proportional to the dose, constant over time and characterized by low individual variability. When using lacosamide 2 times a day Css in plasma are reached within 3 days. Cumulation is accompanied by an increase in plasma concentration of about 2 times.
Css when using a single loading dose of 200 mg is comparable to that when administered orally 100 mg 2 times a day.
Special patient groups
Floor. Clinical studies show that sex does not have a significant effect on plasma lacosamide concentration.
Race. There are no clinically significant differences in the pharmacokinetics of lacosamide in the Asian, Negroid, and Caucasoid races.
Impaired renal function. The AUC value increases to approximately 30% with mild and moderate renal failure and up to 60% with severe and end-stage renal failure requiring hemodialysis, compared with healthy patients, while Cmax does not change. Lacosamide is removed from plasma by hemodialysis. During 4 hours of hemodialysis, the AUC decreases by approximately 50%. Therefore, an additional dose is recommended after the hemodialysis procedure. In patients with moderate and severe renal insufficiency, the release 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 24-hour follow-up. It has not been fully studied whether reduced excretion of a metabolite in patients with end-stage renal failure leads to a change in the number of side effects, but O-demethylmetabolite was confirmed to have no pharmacological activity.
Liver dysfunction. In patients with moderate hepatic impairment, elevated plasma plasma levels of lacosamide were observed (approximately 50% increase in AUC). One of the reasons for the increased exposure was a decrease in renal function in patients who participated in the studies. The decrease in non-renal clearance in patients from the study was evaluated as an increase in AUC of lacosamide by 20%. In patients with severe liver failure, pharmacokinetics have not been studied.
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 with young patients. This is partly due to reduced body weight, 26% in men and 23% in women from normal body weight. In studies in elderly patients, the renal clearance of lacosamide was reduced slightly.
Vimpat®® in the form of infusions prescribed in those cases where it is temporarily impossible to take the drug inside.
Excipients: microcrystalline cellulose, low substituted hyprolose, brine HD 90 (microcrystalline cellulose, anhydrous colloidal silicon dioxide), crospovidone, magnesium stearate, hyprolose
Film coating composition: opadry II 85G20182 purple (polyvinyl alcohol, talc, macrogol 3350, soy lecithin, titanium dioxide (E171), iron dye red oxide (E172), iron dye black oxide (E172), indigo carmine dye FD & C blue 2) opadry YS-3-7413 transparent (macrogol 400, macrogol 8000, hypromellose 3 cf, hypromellose 6 cf, hypromellose 50 cf).
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Dosage and Administration
Vimpat® is taken orally. The daily dose is divided into 2 doses - in the morning and in the evening, regardless of the meal time. 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. Taking into account the effectiveness and tolerability, the maintenance dose can be increased to 150 mg 2 times a day in the third week of administration and up to a maximum daily dose of 400 mg / day (200 mg 2 times a day) from the fourth week. Abolishing Vimpat® is recommended gradually, reducing the dose by 200 mg per week.
With lacosamide treatment, the most frequent adverse reactions were dizziness, headache, nausea, and diplopia. As a rule, they were mild or moderately pronounced. The severity of some adverse reactions depended on the dose and decreased after its decrease. The frequency and severity of adverse reactions from the central nervous system and the digestive system usually decreased with time.
The use of lacosamide is accompanied by a dose-dependent prolongation of the PR interval, as a result of which the development of such clinical conditions as AV blockade, syncope and bradycardia is possible.
Adverse reactions noted in more than 1% of patients in clinical studies are listed below. Determination of the frequency of adverse reactions: very often (≥1 / 10); often (≥1 / 100 to
From the side of the central nervous system: very often - dizziness, headache; often - depression, irritability, imbalance, impaired motor coordination, impaired memory, impaired attention, cognitive impairment, hypoesthesia, drowsiness, confusion, tremor, nystagmus, dysarthria.
From the senses: very often - diplopia; often - blurred vision, vertigo, tinnitus.
On the part of the digestive system: very often - nausea; often - vomiting, constipation, flatulence, dyspepsia, dry mouth.
Dermatological reactions: often - itching.
On the part of the musculoskeletal system: often - muscle spasms.
Other: often - violation of gait, asthenia, fatigue, falls, increased risk of injury (due to impaired coordination of movements and dizziness).
The drug should be used with caution in patients with severe renal insufficiency (CC ≤ 30 ml / min), with conduction disorders, heart failure and myocardial infarction in history. 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 prolonged PR interval.Application for violations of the liver
Research results indicate a low probability of the interaction of lacosamide with other drugs.
In preclinical studies, synergism or additive anticonvulsant action was observed in combination with levetiracetam, carbamazepine, phenytoin, valproic acid, lamotrigine, topiramate, gabapentin.
Lakosamid should be used carefully 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 lengthening of the PR interval was observed in patients who simultaneously took lacosamide in combination with carbamazepine or lamotrigine.
Lacosamide is a substrate of cytochrome P450 (CYP2C19).
Powerful enzyme inducers, such as rifampicin or Hypericum perforatum (Hypericum perforatum), can cause a moderate decrease in the systemic concentration of lacosamide. In this regard, the appointment of such drugs or their cancellation should be careful.
Lacosamide at any therapeutic dose has no effect on Css plasma anticonvulsants, incl. levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine, phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam and zonisamide.
Carbamazepine and valproic acid had no effect on plasma lacosamide concentration.
Concomitant therapy with anticonvulsant enzyme-inducing agents (carbamazepine, phenytoin, phenobarbital in various doses) reduced the overall systemic exposure of lacosamide by 25%.
There were no signs of significant interaction between lacosamide and oral contraceptives ethinyl estradiol and levonorgestrel. Lacosamide has no effect on progesterone concentration.
Lacosamide does not affect the pharmacokinetics of digoxin.
No clinically significant interaction of lacosamide and metformin has been identified.
There is no data on the interaction of lacosamide with ethanol.
Omeprazole in a dose of 40 mg 1 time / day increased the AUC of lacosamide by 19%. This effect may not have clinical significance. When taking a single dose, lacosamide did not affect the pharmacokinetics of omeprazole. The effect of other cytochrome P450 isoenzymes and other enzymes on the metabolism of lacosamide 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%. In this regard, a clinically significant interaction with other drugs that bind to proteins is unlikely.
Pregnancy and Lactation
Clinical data on the use of lacosamide during pregnancy is not available. Lakosamid should not be used during pregnancy, except in cases where the benefits to the mother clearly outweigh the possible risk to the fetus.
If a woman is planning a pregnancy, it is necessary to carefully weigh the feasibility of using this drug.
In experimental studies, no teratogenic effects were recorded, however, embryotoxicity was observed when used in high (toxic) doses.
Data on the allocation of lacosamide with human breast milk are not available. Experimental studies noted the excretion of lacosamide in breast milk.
During treatment with lacosamide, breastfeeding should be discontinued.
Treatment with lacosamide may be accompanied by dizziness, potentially resulting in injuries and falls. In this regard, patients should be careful.
Analysis of data from clinical studies of anticonvulsant drugs indicates a slight increase in the risk of suicidal thoughts and suicidal behavior. The mechanism to increase the risk is not clear, the existing data do not allow to deny the existence of such a risk when taking lacosamide. Persons caring for patients should be warned about the risks and the need to consult a specialist if suicidal behavior occurs. Patients receiving treatment with lacosamide should be carefully monitored and warned to consult a specialist if suicidal thoughts occur.
Considering the possibility of lengthening the PR interval against the background of therapy with Vimpat®®Patients are recommended periodic ECG monitoring.
Syrup contains sodium propyl parahydroxybenzoate (E217) and sodium methyl parahydroxybenzoate (E219) excipients, which can cause allergic reactions (including those of a delayed type). Syrup contains 3.7 g of 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 diet restricting sodium intake.
Use in Pediatrics
Lakosamid is not recommended to appoint children and adolescents under the age of 16 years, because safety and efficacy of the drug in these age groups have not been studied.
Influence on ability to drive motor transport and control mechanisms
The drug can 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 machinery.
Clinical data on overdose of lacosamide is limited.
Symptoms: after taking the drug in a dose of 1200 mg / day - mostly dizziness and nausea, which disappeared after reducing the dose. During the clinical trials, a single dose of lacosamide was registered at a dose of 12 g, which was taken along with the toxic doses of other antiepileptic drugs. The patient fell into a coma, but then fully recovered without consequences.
Treatment: there is no antidote to lacosamide; conduct symptomatic therapy; if necessary, hemodialysis can be used.
- Brand name: Vimpat®
- Active ingredient: Lacosamide
- Dosage form: pills, film-coated pinkish, oval, biconvex, with the extruded marking "50" on one side and "SP" - on the other.
- Manufacturer: YUSB Farshim S.A.
- Country of Origin: Belgium
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