Vimpat®
For oral administration
The daily dose is divided into 2 doses - morning and evening, regardless of the time of meal.
The recommended starting dose is 50 mg 2 times/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 when taking tablets, it can be increased to 150 mg 2 times / day in the third week of administration, 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.
It is recommended to discontinue Vimpat® gradually, reducing the dose by 200 mg per week.
For intravenous administration
Injected intravenously for 15-60 minutes 2 times a day.
The recommended starting dose is 50 mg 2 times/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 every week by 50 mg 2 times / day to a maximum daily dose of 400 mg (200 mg 2 times / day). It is recommended to discontinue Vimpat® gradually (reducing the dose by 200 mg per week).
The solution can be administered without additional dilution or diluted.
There is experience in using the solution for infusions for up to 5 days. You should switch to taking the drug orally as soon as possible.
Treatment with Vimpat® can be started either by taking tablets orally or by intravenously administering a solution for infusion.
If necessary, you can replace taking tablets intravenously without re-titrating the dose and vice versa. In this case, you should not change the daily dose and frequency of use (2 times/day).
When taken orally and when administered intravenously
patients with mild to moderate
renal impairment (creatinine clearance >30 ml/min)
do not require dose adjustment.
In patients with severe renal failure (creatinine clearance ≤30 ml/min),
the maximum dose is 300 mg/day.
Lacosamide is removed from plasma during hemodialysis, and within 4 hours after the procedure, AUC decreases by approximately 50%. For patients undergoing hemodialysis,
it is recommended to prescribe an additional 50% of the single dose immediately after the end of the procedure.
Treatment of patients with severe renal failure
should be carried out with caution, because clinical experience with 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, dose titration is recommended with caution.
When taken orally and when administered intravenously
For patients with
mild to moderate liver dysfunction,
no dose adjustment is required.
Dose titration in such patients should be done with caution, given that impaired liver function is often accompanied by impaired renal function. The pharmacokinetics of lacosamide in patients with severe hepatic impairment
have not been studied.
When taken orally and when administered intravenously
Elderly patients
do not require dose reduction.
Experience with lacosamide in elderly patients with epilepsy is limited. In elderly people, it is necessary to take into account the possibility of an age-related decrease in renal clearance and, as a result, an increase in the concentration of lacosamide in the blood plasma. Rules for preparing infusion solution
Before administering the drug, make sure that the solution in the bottle is transparent, colorless and does not contain foreign impurities. Otherwise, do not use this bottle.
Vimpat® solution for infusion is compatible with the following solvents: 0.9% sodium chloride solution, 5% dextrose solution, lactated Ringer's solution.
The prepared solution should be used within 24 hours after dissolution when stored in glass or polyvinyl chloride bottles at a temperature not exceeding 25°C.
Unused solution should be disposed of in accordance with existing regulations.
Vimpat, 14 pcs., 100 mg, film-coated tablets
Pharmacodynamics
The active substance is 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 selectively enhances the slow inactivation of voltage-gated sodium channels, leading to the stabilization of hyperexcitable neuronal membranes.
In most cases of animal modeling, lacosamide prevented the development of attacks of partial and primary generalized epilepsy, and also delayed the development of increased convulsive readiness. In preclinical studies, lacosamide interacted with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, topiramate or gabapentin to demonstrate synergistic additive anticonvulsant effects.
Clinical efficacy and safety
The effectiveness of Vimpat ® as an adjunctive therapy at recommended doses (200, 400 mg/day) has been proven in 3 multicenter, randomized, placebo-controlled clinical studies 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 1308 patients with a history of partial-onset seizures over a mean period of 23 years, were designed to evaluate the efficacy and safety of lacosamide when co-administered with 1 to 3 antiepileptic drugs in patients with uncontrolled partial-onset 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.
The pharmacokinetics and safety of a single loading dose of lacosamide infusion were determined in a multicenter, open-label study of the safety and tolerability of rapid initiation of lacosamide therapy using a single IV loading dose (200 mg), followed by twice daily oral administration of the drug (at a dosage equivalent to IV dose) as adjunctive therapy in adult patients 16 to 60 years of age with partial-onset seizures.
Pharmacokinetics
Suction
Solution for infusion. Cmax is reached by the end of the infusion. Plasma concentrations of lacosamide increase proportionally to the dose after intravenous (50–300 mg) administration.
Film-coated tablets. Lacosamide is rapidly and completely absorbed after oral administration. The bioavailability of lacosamide in tablets is approximately 100%. After oral administration, the plasma concentration of lacosamide increases rapidly, T max - 0.5–4 hours. 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 in the form of O-desmethyl metabolite (less than 30%). The polar fraction (presumably serine derivatives) constitutes approximately 20% in the urine and is only found in small quantities (0–2%) in the blood plasma. Other metabolites are detected in urine in an amount of 0.5–2%.
In vitro data show that the formation of O-desmethyl metabolite occurs mainly under the influence of cytochrome isoenzymes CYP2C19, 2C9 and 3A4. When comparing the pharmacokinetics of lacosamide in extensive metabolizers (with a functional isoenzyme of the cytochrome CYP2C19) and slow metabolizers (with a deficiency of the functional isoenzyme of the cytochrome CYP2C19), no clinically significant difference in the excretion of lacosamide was noted. In addition, interaction studies with omeprazole (an inhibitor of the CYP2C19 isoenzyme) showed no clinically significant changes in lacosamide plasma concentrations, indicating the low significance of this pathway.
The concentration of O-desmethyl metabolite in plasma is approximately 15% of the concentration of lacosamide. This metabolite has no pharmacological activity.
Removal
Lacosamide is eliminated by renal excretion and biotransformation. After oral and intravenous administration of radiolabeled lacosamide, approximately 95% of the radioactivity was observed in the urine and less than 0.5% in the feces. T1/2 of unchanged lacosamide is approximately 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, C ss in plasma is achieved within 3 days. Cumulation is accompanied by an increase in plasma concentration by approximately 2 times.
C ss when using a single loading dose of 200 mg is comparable to that when taking 100 mg orally 2 times a day.
Special patient groups
Floor. Clinical studies show that gender does not have a significant effect on lacosamide plasma concentrations.
Race. There are no clinically significant differences in the pharmacokinetics of lacosamide in Asian, Negroid and Caucasian races.
Renal dysfunction. The AUC value increases to approximately 30% in mild to moderate renal failure and up to 60% in severe and end-stage renal failure requiring hemodialysis compared with healthy patients, while Cmax does not change. Lacosamide is removed from plasma during hemodialysis. Within 4 hours of hemodialysis, AUC decreases by approximately 50%. Therefore, after the hemodialysis procedure, it is recommended to take an additional dose. In patients with moderate and severe renal failure, the excretion of O-desmethyl metabolite decreased several times. In patients with end-stage renal disease without hemodialysis, levels were increased and increased continuously during 24-hour follow-up. It has not been fully studied 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 has been confirmed that O-desmethyl metabolite does not have pharmacological activity.
Liver dysfunction. Increased lacosamide plasma concentrations (approximately 50% increase in AUC) were observed in patients with moderate hepatic impairment. One reason for the increased exposure was decreased renal function in patients participating in the studies. The decrease in non-renal clearance in study patients was estimated as a 20% increase in lacosamide AUC. Pharmacokinetics have not been studied in patients with severe hepatic impairment.
Elderly patients. The studies involved 4 elderly patients over 75 years of age. AUC was increased by ≥30% in men and 50% in women compared with younger patients. This is partly explained by 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.
Vimpat tablets 100 mg 14 pcs. in St. Petersburg
Lacosamide should be used cautiously in combination with drugs that cause a prolongation of the PR interval (for example, carbamazepine, lamotrigine, pregabalin) and in patients receiving class I antiarrhythmic drugs. However, in a subgroup analysis of clinical trials, no additional prolongation of the PR interval was observed in patients who simultaneously took lacosamide in combination with carbamazepine or lamotrigine.
In vitro data
Research results indicate a low likelihood of interaction between lacosamide and other drugs. In vitro metabolism studies show that lacosamide does not induce CYP1A2, 2B6 and 2C9 isoenzymes. At the concentrations observed in the blood during clinical studies, lacosamide did not inhibit CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6 and 2E1 isoenzymes. In vitro studies indicate that lacosamide is not transported by P-glycoprotein in the intestine. In vitro data
show that the isoenzymes CYP2C9, CYP2C19 and CYP3A4 are capable of catalyzing the formation of O-desmethyl metabolite.
In vivo data
Clinical data indicate that lacosamide does not inhibit or induce CYP2C19 and 3A4 isoenzymes to clinically significant levels. Lacosamide had no effect on the AUC of midazolam (metabolized via the CYP3A4 isoenzyme, at a dosage of lacosamide 200 mg 2 times a day), but the Cmax of midazolam was slightly increased (30%). Lacosamide does not affect the pharmacokinetics of omeprazole (metabolized through isoenzymes CYP2C19 and 3A4, at a dosage of lacosamide 300 mg 2 times a day).
Omeprazole, an inhibitor of the CYP2C19 isoenzyme (40 mg 4 times a day), did not significantly increase the exposure of lacosamide to a clinically significant extent. Thus, it is unlikely that moderate inhibitors of the CYP2C19 isoenzyme can affect the systemic exposure of lacosamide to a clinically significant level.
Caution should be exercised during simultaneous use with potent inhibitors of the CYP2C19 isoenzyme (for example, fluconazole) and the CYP3A4 isoenzyme (for example, itraconazole, ketoconazole, ritonavir, clarithromycin), which may lead to an increase in the systemic exposure of lacosamide. These interactions have not been demonstrated in vivo
, but are possible based on
in vitro data.
Potent inducers of liver microsomal enzymes, such as rifampicin or St. John's wort (Hypericum perforatum), may cause a moderate decrease in systemic concentrations of lacosamide. In this regard, caution should be exercised when prescribing or discontinuing such drugs.
Antiepileptic drugs
In interaction studies, lacosamide did not have a significant effect on plasma concentrations of carbamazepine and valproic acid. Carbamazepine and valproic acid had no effect on lacosamide plasma concentrations. A population pharmacokinetic analysis proved that concomitant therapy with antiepileptic drugs that induce microsomal liver enzymes (carbamazepine, phenytoin, phenobarbital in various doses) reduced the total systemic exposure of lacosamide by 25%.
Oral contraceptives
There were no signs of significant interaction between lacosamide and oral contraceptives: ethinyl estradiol and levonorgestrel. Lacosamide has no effect on progesterone concentrations.
Other interactions
Lacosamide does not affect the pharmacokinetics of digoxin. No clinically significant interaction between lacosamide and metformin has been identified. There is no data on the interaction of lacosamide with alcohol. The degree of binding of lacosamide to plasma proteins is less than 15%. In this regard, clinically significant interaction with other drugs that bind to plasma proteins is unlikely.
