Wimpat® (Vimpat®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceLacosamideLacosamide
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  • Wimpat®
    syrup inwards 
    YUSB Farma S.A.     Belgium
  • Wimpat®
    pills inwards 
    YUSB Farma S.A.     Belgium
  • Wimpat®
    solution d / infusion 
    YUSB Farma S.A.     Belgium
    • Dosage form: & nbspsolution for infusions
    Composition:
    1 ml of the solution contains:
    active substance: lacosamide 10.0 mg;
    Excipients: sodium chloride 7.62 mg, hydrochloric acid diluted (10.0%) to pH 4.0, water for injection up to 1.0 ml.
    Description:A clear, colorless solution.
    Pharmacotherapeutic group:Antiepileptic remedy
    ATX: & nbsp

    N.03.A.X   Other antiepileptic drugs

    N.03.A.X.18   Lacosamide

    Pharmacodynamics:
    Active substance - lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide) is a functionalized amino acid.
    The exact mechanism of antiepileptic action of lacosamide is not established. In electrophysiological studies in vitro lacosamide selectively enhances the slow inactivation of the potential-dependent sodium channels, which leads to the stabilization of hyperexcitable neuronal membranes.
    Pharmacodynamics
    Lacosamid prevented the development of seizures on a large number of animal models of partial and primarily generalized epilepsy, and also delayed the development of increased convulsive readiness. In preclinical studies lacosamide in combination with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, gopiramate or gabapentin demonstrated synergistic or additive anticonvulsant action.
    Clinical efficacy and safety
    The efficacy of Wimpat® as an adjunctive therapy at recommended doses (200 mg / day, 400 mg / day) was demonstrated in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. Efficacy Vimpat® drug in a dose of 600 mg / day has also been shown in controlled additional therapeutic studies, although the efficacy was comparable to a dose of 400 mg / day, but the tolerability of this dose (600 mg / day) but was worse due to side effects from 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 partial seizures develop during an average period of 23 years, it was designed to evaluate the efficacy and safety of lakosamida atconcomitant administration of 1-3 antiepileptic drugs in patients with uncontrolled partial seizures with or without secondary generalization. The total proportion of patients with a 50% reduction in seizure frequency in the placebo groups, lacosamide 200 mg / day, and lacosamide 400 mg / day was 23%, 34% and 40%, respectively.
    Currently, there is insufficient data on the possible withdrawal of concomitant antiepileptic drugs for the use of monotherapy with lacosamide.
    The pharmacokinetics and safety of a single saturating dose of the infusion lacosamid were determined in a multicenter open safety study and the tolerability of the rapid onset of lacosamide therapy using a single intravenous saturating dose (200 mg) followed by oral administration of the drug 2 times a day (at an equivalent equivalent intravenous dose) as an additional therapy in adult patients from 16 to 60 years with partial seizures.
    Pharmacokinetics:Suction

    The maximum concentration (CmOh) is reached by the end of the infusion. The concentration of lacoside in plasma increases in proportion to the dose after intravenous(50-300 mg) of administration.

    Distribution

    The volume of distribution is approximately 0.6 l / kg, the degree of binding to proteins plasma - less than 15%.

    Metabolism

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

    Data in vitro show that the formation of O-desmethyl metabolite occurs mainly under the action of cytochrome isoenzymes CYP2C19, 2C9 and 3A4. When comparing the pharmacokinetics of lacoside in extensive metabolizers (with a functional isoenzyme of cytochrome CYP2C19) and slow metabolizers (with a deficiency of the functional isoenzyme of cytochrome CYP2C19) there was no clinically significant difference in lacosamide release. In addition, studies on the interaction with omeprazole (inhibitor of isoenzyme CYP2C19) showed no clinically significant changes in the concentration of lacosamide in plasma, which indicates a 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.

    Excretion

    Lacosamide is excreted by renal excretion and biotransformation. After oral administration and intravenous administration of lacosamide labeled with a radioactive isotope, about 95% of the radioactivity was noted in the urine and less than 0.5% in the feces. The period of the elimination of unchanged lacosamide is approximately 13 hours. Pharmacokinetic parameters are proportional to the dose, constant in time and characterized by low individual variability. When using lakosamid twice a day, equilibrium concentrations in the plasma are reached within 3 days. Cumulation is accompanied by an increase in the concentration in the plasma by about 2 times. The equilibrium concentration with a single loading dose of 200 mg is comparable to that for oral administration of 100 mg twice a day.

    Pharmacokinetics in specific patient groups

    Floor

    Clinical studies show that sex does not have a significant effect on the concentration of lacosamide in blood plasma.

    Race

    Clinically significant differences in the pharmacokinetics of lacoside in Asian, Negroid and Caucasoid races are absent.

    In patients with renal insufficiency

    The value of the "area under the concentration-time ratio curve" (AUC) increases to approximately 30% with mild and moderate renal failure and up to 60% in the severe and terminal stage of renal failure requiring hemodialysis, compared with healthy patients, while Cmax does not change. Lacosamide is removed from the plasma during hemodialysis. Within 4 hours of hemodialysis, the area of ​​iodine of the concentration-time curve decreases by approximately 50%. Therefore, after the procedure of hemodialysis, an additional dose is recommended. In patients with moderate and severe renal failure, the release of O-desmethyl metabolite increased several fold. In patients with terminal stage of renal failure in the absence of hemodialysis, the levels were increased and continuously increased during a 24-hour observation. It has not been studied before the shock whether increased release of the metabolite in patients with end-stage renal failure can lead to an increase in the number of side effects, but it has been confirmed,that the pharmacological activity of O-desmethyl metabolite does not possess.

    In patients with hepatic insufficiency

    In patients with moderate hepatic insufficiency, increased concentrations of lacoside in blood plasma (approximately 50% more AUCstandards). One of the reasons for the increased exposure was a decrease in renal function in patients who participated in the studies. Reduction of the non-obese clearance in patients from the study was estimated as an increase AUC lacosamide by 20%. Patients with severe hepatic insufficiency did not study pharmacokinetics.

    In elderly patients

    Four elderly patients over the age of 75 took part in the studies. AUC was increased by about 30% in men and 50% in women compared with young patients. Partly this is due to reduced body weight, 26% in men and 23% in women from normal body weight. There was also an increased outputlacosamide. In studies in elderly patients, the renal clearance of lacosamide was reduced only slightly.

    Indications:As an additional therapy for partial convulsive seizures, accompanied or not accompanied by secondary generalization, in patients with epilepsy aged 16 years and older.
    Contraindications:
    Hypersensitivity to the active substance or to any of the components of the drug.
    Atriovengricular block of II or III degree.
    Age to 16 years.
    Carefully:In patients with severe renal failure (creatinine clearance ≤ 30 ml / min). In patients with a history of conduction disorder or severe heart disease, such as heart failure and myocardial infarction in history. Elderly patients with an increased risk of heart disease. In combination with drugs that cause prolongation of the PR interval.
    Pregnancy and lactation:

    Pregnancy

    The general risk associated with epilepsy and antiepileptic medicines

    For all antiepileptic drugs, it was shown that the frequency of congenital malformations in children of women with epilepsy receiving such therapy is 2-3 times higher than in the general population (in the latter case, this figure is 3%). In patients receiving treatment, there was an increase in the incidence of congenital malformations in children amid polytherapy, but the extent of the effect of treatment and / or disease on the increase of this risk is unknown to date.

    In addition, effective antiepileptic treatment should not be stopped, as the deterioration of the course of the disease has a negative effect on the mother and on the fetus.

    The risk associated with the use of lacosamide

    There are no clinical data on the use of lacosamide in pregnant women. Teratogenic effects were not recorded in animal studies, but when applied doses toxic to the maternal organism, embryotoxicity was noted in rabbits and rats. Potential risk to people is unknown. Lacosamide Do not use during pregnancy, except when the benefit to the mother clearly outweighs 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. To monitor the effects of Vimpat® in pregnant women, it is recommended that doctors register patients' data in the European and International Registry for antiepileptic drugs and pregnancy (EURAP).

    Lactation period

    Data on the excretion of lacoside with human breast milk are absent.In studies on animals, excretion of lacosamide with milk was noted. During lacosamide treatment, breastfeeding should be discontinued.

    Fertility

    No adverse reactions have been observed on the part of fertility or reproductive performance in rats of both sexes in doses that create a concentration in the plasma (AUC) approximately 2 times higher AUC in human plasma with the application of the maximum recommended dose for humans.

    Dosing and Administration:

    Wimpat ® solution for infusion is prescribed in cases when oral therapy is temporarily impossible.

    Intravenously for 15-60 minutes 2 times a day.

    The recommended starting dose is 50 mg 2 times a day. After 1 week, increase to 100 mg 2 times a day.

    Lacosimide treatment can also be started with a single saturating dose of 200 mg, followed by the appointment of approximately 100 mg twice a day (200 mg / day) of a maintenance dosage regimen after approximately 12 hours. The saturation dose can be used in patients in situations where the doctor determines that rapid achievement of equilibrium concentration in the plasma and the therapeutic effect is guaranteed. This should be used under medical supervision, given the possible increase in the number of unwanted reactions from the central nervous system.The appointment of a saturating dose has not been studied in acute conditions, such as epileptic status.

    Taking into account the effectiveness and tolerability, the maintenance dose can be increased every week by 50 mg twice a day to a maximum daily dose of 400 mg / day (200 mg twice a laziness). To abolish Wimpat® is recommended gradually (reducing the dose by 200 mg per pedel).

    The solution can be administered without additional dilution or diluted. There is experience in using a solution for infusions lasting up to 5 days. It should be switched to oral intake of the drug as soon as it becomes possible. Treatment with WIMPAT® can be started both with the intake of tablets inside, and with an intravenous infusion solution.

    If necessary, you can replace the reception of tablets by intravenous administration without repeated titration of the dose and vice versa. In this case, do not change the daily dose and the frequency of application (twice a day).

    Instructions for preparing a solution

    Before administering the drug, make sure that the solution in the bottle is clear and colorless, and does not contain foreign impurities. If not, do not use this vial.

    Vimpat infusion solution is compatible with the following solvents:

    - 0.9% solution of sodium chloride,

    - 5% dextrose solution,

    - Ringer's solution is lactate.

    The prepared solution should be used within 24 hours after dissolution when stored in vials of glass or polyvinyl chloride at a temperature of no higher than 25 ° C.

    The unused solution must be disposed of in accordance with existing regulations.

    Use in patients with renal insufficiency

    Patients with mild and moderate renal impairment (creatinine clearance> 30 ml / min) do not need dose adjustment. Patients with mild and moderate renal dysfunction may consider the appointment of a saturating dose of 200 mg, but further titration of the dose (> 200 mg / day) should be conducted with caution. In patients with severe renal insufficiency (creatinine clearance ≤30 ml / min) and patients with terminal stage of renal failure the maximum dose is 250 mg / day. In these patients, dose titration should be performed with caution. If the purpose of the saturating dose is indicated, the initial dose is 100 mg, followed by 50 mg twice daily for the first week.Patients on hemodialysis are advised to additionally administer up to 50% of a single dose immediately after the end of the procedure. Treatment of patients with terminal stage of renal failure should be conducted with caution, since the clinical experience of using the drug in such patients is small, and possibly the accumulation of a metabolite that does not have a known pharmacological activity.

    The use of patients with impaired hepatic function

    Patients with mild to moderate liver dysfunction do not need dose adjustment. Titrate the dose to such patients with caution, given the concomitant impairment of kidney function. It is possible to administer a saturating dose of 200 mg, but further titration of the dose (> 200 mg / day) is recommended with caution.

    The pharmacokinetics of lacoside in patients with severe hepatic insufficiency has not been studied.

    Application in the elderly

    Elderly, a dose reduction is not required. The 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 consequence, an increase in the concentration of lacosamide in blood plasma.

    The use of children

    Lacosamides are not recommended for children and adolescents under the age of 16 because the safety and efficacy of the drug in these age groups have not been studied.

    Side effects:

    Based on an analysis of pooled placebo-controlled clinical trials. when treating with lacosamide, the most frequent 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 (CNS) and gastrointestinal tract usually decreased with time. The most frequent undesirable reaction leading to the abolition of lacosamide therapy was dizziness. The percentage of adverse reactions from the central nervous system, such as dizziness, may be higher after applying a saturating dose

    Adverse reactions are classified according to the following categories: very often (≥1/10); often (from ≥1/100 to <1/10); infrequently ≥1/1000 to <1/100), the frequency is unknown.The frequency of the following adverse reactions is indicated in accordance with the data obtained during clinical trials and in post-marketing practice.

    On the part of the blood and lymphatic system

    The frequency is unknown: agranulocytosis.

    From the immune system

    Infrequent: hypersensitivity reactions.

    Frequency unknown: hypersensitivity reactions with lesions of different organs and systems (including drug reaction with eosinophilia and systemic manifestations, DRESS).

    Disorders of the psyche:

    Often: depression, confusion, insomnia.

    Infrequently: aggression, excitement, euphoria, mental disorders, suicidal attempts, suicidal thoughts, hallucinations.

    From the central nervous system

    Very often: dizziness, headache.

    Common: impaired balance, incoordination, memory impairment, cognitive disorder, somnolence, tremor, nystagmus, gppesteziya, dysarthria, disturbance of attention, paresthesia.

    From the side of the organ of vision

    Very often: diplopia.

    Often: blurred vision.

    From the side of the hearing and vestibular organs

    Often: vertigo, noise in the ears.

    From the heart

    Infrequently: atrioventricular block, bradycardia, atrial fibrillation and flutter.

    From the gastrointestinal tract

    Very often: nausea.

    Often: vomiting, constipation, flatulence, indigestion, dry mouth, diarrhea.

    From the liver and biliary tract

    Infrequent: changes in hepatic samples.

    From the skin and subcutaneous fat

    Often: itching, rash.

    Infrequently: angioedema, hives.

    The frequency is unknown: toxic epidermal necrolysis, Stevens-Johnson syndrome.

    From the musculoskeletal and connective tissue

    Often: muscle spasms.

    General disorders and disorders at the site of administration

    Often: a violation of gait, asthenia, fatigue, irritability, a feeling of intoxication, pain or discomfort, irritation of the skin at the injection site.

    Infrequent: redness of the skin at the injection site. Trauma, intoxication and complications of manipulation

    Often: falls, skin lesions / increased risk of injury (due to impaired coordination of movements and dizziness), bruises.

    Description of selected adverse reactions

    The use of lacosamide is associated with dose-dependent lengthening of the interval PR. There may be side effects associated with lengthening the interval PR (for example, atrioventricular blockade, syncope, bradycardia).

    In clinical studies in patients with epilepsy, the percentage of episodes of grade I atrioventricular blockade was low (0.7%, 0%, 0.5%, and 0% with lacosamide at 200 mg, 400 mg, 600 mg and placebo, respectively. Atrioventricular blockade of II degree and higher in these studies was not observed. Nevertheless, in postmarketing practice, cases of the emergence of atrioventricular blockade of II and III degree in the treatment with lacosamide were reported. In clinical studies, syncope was infrequent and the incidence of episodes did not differ in epileptic patients who received lacosamide (0.1%) and those receiving placebo (0.3%).

    Atrial fibrillation and flutter was not observed in short-term clinical studies; however, both phenomena were noted in open epilepsy studies, as well as in post-marketing practice.

    Deviations of laboratory indicators

    In controlled trials, there was a change in hepatic samples in adult patients with partial convulsive attacks with 1 to 3 antiepileptic drugs at a time. Increase ALT 3 times or more was observed in 0.7% (7/935) patients taking Wimpat ®, and 0% (0/356) taking placebo.

    Hypersensitivity reactions with damage to various organs and systems

    Hypersensitivity reactions were noted with the defeat of various organs and systems (including a drug reaction with eosinophilia and systemic manifestations, DRESS) in patients who received some antiepileptic drugs. These reactions are different in manifestation, but are most often manifested in the form of heat and rash and may affect other systems. If there is a suspicion of a hypersensitivity reaction with the damage of various organs and systems, then the use of lacosamide should be discontinued.

    Overdose:
    Clinical Trials Data
    The profile of adverse reactions in patients taking supertherapeutic doses did not differ from the profile of adverse reactions in patients taking the recommended doses.
    After taking the drug at a dose of 1200 mg / day, clinical symptoms from the central nervous system and the gastrointestinal tract (dizziness and nausea), which disappeared after a dose reduction, were observed.
    The highest declared overdose of lacosamide in the program of clinical development was 12000 mg, taken together with toxic doses of other antiepileptic drugs. Initially, there was atrioventricular blockade, the patient fell into a coma, and then completely recovered without irreversible consequences.
    Post-marketing application data
    As a result of acute overdose after taking the drug in doses from 1000 mg to 12000 mg, convulsions (generalized tonic-clonic seizures, epilepticus status) and conduction disorders of the heart were noted.
    Fatal cardiac arrest was observed in acute overdose after taking 7000 mg of lacosamide in a patient with cardiovascular risk factors.
    Treatment
    The antidote of lacosamide does not exist. Treatment of an overdose is symptomatic. If necessary, hemodialysis is possible.
    Interaction:Lacosamide should be used cautiously in combination with drugs that cause prolongation of the PR interval (eg, carbamazepine, lamotrigine, pregabalin) and in patients receiving class I antiarrhythmic drugs.However, in the subgroup analysis of clinical trials no additional lengtheninginterval PR in patients who simultaneously took lacosamide in combination with carbamazepine or lamotrigine.

    Data in vitro

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

    Metabolic Studies in vitro show that lacosamide does not induce isoenzymes CYP1A2, 2B6 and 2C9. In concentrations that were observed in the blood during clinical trials, lacosamide did not inhibit isoenzymes CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6 and 2E1. Research in vitro indicate that lacosamide is not transported by the P-glycoprotein in the intestine. Data in vitro show that isoenzymes CYP2C9, CYP2C19 and CYP3A4 can catalyze the formation of O-desmethyl metabolite.

    Data in vivo

    Clinical evidence suggests that lacosamide Does not inhibit or induce isoenzymes CYP2C19 and ZA4 to a clinically significant level. Lacosamide does not affect the area under the curve (AUC) Midazolam (metabolized via isoenzyme CYP3A4, with a dosage of lacosamide 200 mg twice daily), but Cmax Midazolam was slightly increased (30%). Lacosamide does not affect the pharmacokinetics of omeprazole (metabolized via isoenzymes CYP2C19 and ZA4, with the dosage of lacosamide 300 mg twice daily). Omeprazole - inhibitor of isoenzyme CYP2C19 (40 mg 4 times a day) did not increase the clinically significant exposure of lacosamide. Thus, it is unlikely that moderate isoenzyme inhibitors CYP2C19 can affect the systemic exposure of lacoside to a clinically significant value.

    Caution should be exercised when using simultaneously with potent inhibitors of isoenzyme CYP2C19 (e.g., flucoazole) and isoenzyme CYP3A4 (eg, itraconazole, ketoconazole, ritonavir, clarithromycin), which can lead to an increase in the systemic exposure of lacoside. These interactions are not proved in vivo, but possible on the basis of data in vitro.

    Powerful inducers of microsomal liver enzymes, such as rifampicin or St. John's wort (Hypericum perforatum), can cause a moderate decrease in the systemic concentration of lacoside. In this regard, when prescribing such drugs or their withdrawal should be careful.

    Antiepileptic drugs

    In research and interaction lacosamide had no significant effect on the concentration of carbamazepine and valproic acid in blood plasma. Carbamazepine and valproic acid did not affect the concentration of lacosamide in plasma.

    Pharmacokinetic analysis of the population proved that concomitant therapy with antiepileptic drugs inducing microsomal enzymes of the liver (carbamazspine, phenytoin, phenobarbital in various doses) reduced the total system exposure of lacosamide by 25%.

    Oral contraceptives

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

    Other interactions

    Lacosamide does not affect the pharmacokinetics of digoxin. Clinically significant interactions between lacosamide and metformin have not been identified. There is no data on the interaction of lacoside 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.

    When used simultaneously with warfarin lacosamide has no clinically significant effect on the pharmacodynamics and pharmacokinetics of warfarin.

    Special instructions:

    Dizziness

    Treatment with lacosamide may be accompanied by dizziness, potentially leading to an increased incidence of injuries and falls. In this regard, patients should be careful until they experience the potential effects of the drug.

    Heart rhythm and conduction

    In clinical trials of lacoside, an increase in the interval PR. In postmarketing practice, atrioventricular blockade of the second or higher degree was observed. In placebo-controlled studies of lacoside, patients with epilepsy had no fibrillation or atrial flutter, but both were noted in open epilepsy studies, as well as in post-marketing practice.

    It is necessary to inform the patient about the symptoms of atrioventricular blockade of the second degree and higher (a rare or irregular pulse, a feeling of light dizziness and loss of consciousness), as well as symptoms of atrial fibrillation and flutter (palpitation,frequent or irregular heartbeat, shortness of breath). In case of their occurrence it is necessary to consult a doctor.

    Suicidal thoughts and behavior

    In patients who received antiepileptic drugs but several indications, suicidal thoughts and behavior were noted. A meta-analysis of randomized placebo-controlled clinical trials of antiepileptic drugs suggests a slight increase in the risk of suicidal ideation and suicidal behavior. The mechanism of increasing risk is not clear, existing data do not allow to deny the existence of such a risk when taking lacosamide. Therefore, patients should monitor the signs of suicidal thoughts and behavior, and consider the issue of appropriate treatment. Patients and persons caring for patients should be warned about the existing risk and the need for consultation with a specialist in case of suicidal behavior.

    This drug contains 2.6 mmol (or 59.8 mg) of sodium / vial. This fact should be taken into account in patients receiving a diet with sodium content control.

    Effect on the ability to drive transp. cf. and fur:Lacosamide can affect the ability to drive a car or use sophisticated technology. Treatment with lacosamide may be accompanied by the development of dizziness or blurred vision. Accordingly, patients are not advised to drive a car or operate complex equipment.
    Form release / dosage:
    Solution for infusions 10 mg / ml.
    Packaging:
    For 20.0 ml of the preparation in bottles of colorless transparent glass (type I, Hebrew F.) with a capacity of 20 ml, sealed with a chlorobutyl rubber stopper coated with fluoropolymer and rolled up with an aluminum cap provided with a tear-off plastic seal of gray color.
    1 bottle with instructions for use in a cardboard pack.
    Storage conditions:Store at a temperature not exceeding 25 ° C. Keep out of the reach of children.
    Shelf life:
    3 years.
    div> Do not use the drug after the expiry date indicated on the package.
    Terms of leave from pharmacies:On prescription
    Registration number:LSR-009147/09
    Date of registration:13.11.2009 / 26.05.2016
    Expiration Date:Unlimited
    The owner of the registration certificate: YUSB Farma S.A. YUSB Farma S.A. Belgium
    Manufacturer: & nbsp
    Representation: & nbspYUSB FARMA LLC YUSB FARMA LLC Russia
    Information update date: & nbsp15.02.2017
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