Product Overview
Composition
| 1 tab | |
| lacosamide | 150 mg |
Excipients:
microcrystalline cellulose,
low substituted hyprolose,
Prosolv HD 90 (microcrystalline cellulose, silicon dioxide colloidal anhydrous),
crospovidone
magnesium stearate,
hyprolose.
The composition of the film shell:
Opadry II 85G27190 golden (polyvinyl alcohol, talc, macrogol 3350, soy lecithin, titanium dioxide (E171), iron oxide dye yellow (E172), iron oxide dye red (E172), iron oxide black (E172)), opadry YS- 3-7413 transparent (macrogol 400, macrogol 8000, hypromellose 3 sr, hypromellose 6 sr, hypromellose 50 sr).
pharmachologic effect
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Pharmacodynamics
The active substance is 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 in vitro electrophysiological studies, lacosamide enhances the slow inactivation of voltage-gated sodium channels selectively, which leads to stabilization of hyper-excitable neuronal membranes.
Lacosamide in most animal modeling cases 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 conjunction with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, topiramate or gabapentin showed a synergistic additive anticonvulsant effect.
Clinical Efficiency and Safety
The effectiveness of Wimpat ® as an adjunctive therapy at recommended doses (200, 400 mg / day) has been proven in 3 multicenter, randomized, placebo-controlled clinical trials with a 12-week maintenance period. The effectiveness of the drug Wimpat ® a dose of 600 mg / day was also shown during controlled additional therapeutic studies, although the effectiveness was comparable to a dose of 400 mg / day, but the tolerance 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 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 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 placebo groups,
Currently, there is insufficient data on the possibility of canceling concomitant antiepileptic drugs for the use of lacosamide monotherapy.
The pharmacokinetics and safety of a single saturating dose of infusion of lacosamide was determined in a multicenter open-label study of the safety and tolerability of the fast start of lacosamide therapy using a single intravenous saturating dose (200 mg), followed by oral administration of the drug 2 times a day (at a dosage equivalent to iv dose) as adjunctive therapy in adult patients from 16 to 60 years old with partial seizures.
Pharmacokinetics
Suction
Solution for infusion. C max is reached at the end of the infusion. The concentration of lacosamide in plasma increases in proportion to the dose after iv (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 concentration of lacosamide in plasma increases rapidly, T max - 0.5-4 hours. Eating does not affect the rate and degree 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-desmethylmetabolite (less than 30%). The polar fraction (presumably derivatives of serine) is approximately 20% in urine and is found only in small amounts (0–2%) in blood plasma. Other metabolites are determined in the urine in an amount of 0.5–2%.
In vitro data show that the formation of O-desmethylmetabolite occurs mainly under the influence of cytochrome isoenzymes CYP2C19, 2C9 and 3A4. When comparing the pharmacokinetics of lacosamide in extensive metabolizers (with functional isoenzyme of cytochrome CYP2C19) and slow metabolizers (with lack of functional isoenzyme of cytochrome CYP2C19), there was no clinically significant difference in lacosamide excretion. In addition, studies on the interaction with omeprazole (an inhibitor of the CYP2C19 isoenzyme) showed the absence of clinically significant changes in the concentration of lacosamide in plasma, 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 have pharmacological activity.
Breeding
Lacosamide is excreted by renal excretion and biotransformation. After oral administration and iv administration of lacosamide labeled with a radioactive isotope, about 95% of the radioactivity was observed in urine and less than 0.5% in feces. T 1/2 of unchanged lacosamide is approximately 13 hours. Pharmacokinetic parameters are dose-proportional, constant in time and characterized by low individual variability. When using lacosamide 2 times a day, C ss in plasma are reached 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 with oral administration of 100 mg 2 times a day.
Special patient groups
Floor. Clinical studies show that gender does not have a significant effect on the concentration of lacosamide in blood plasma.
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% in mild to moderate renal failure and up to 60% in severe and terminal stages of renal failure requiring hemodialysis, compared with healthy patients, while C max does not change. Lacosamide is removed from plasma by hemodialysis. Within 4 hours of the hemodialysis procedure, AUC decreases by approximately 50%. Therefore, after the hemodialysis procedure, an additional dose is recommended. In patients with moderate and severe renal failure, 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 the 24-hour observation. It has not been fully studied whether reduced metabolite excretion 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.
Impaired liver function. In patients with moderate liver failure, elevated plasma concentrations of lacosamide were observed (increase in AUC by approximately 50%). One of the reasons for the increased exposure was a decrease in renal function in patients participating in the studies. A decrease in renal clearance in patients from the study was evaluated as an increase in AUC of lacosamide by 20%. In patients with severe hepatic impairment, pharmacokinetics has not been studied.
Elderly patients. The study involved 4 elderly patients older than 75 years. AUC was increased by 30 30% in men and 50% in women compared to younger patients. This is partially 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, with or without secondary generalization, in patients with epilepsy from the age of 16 years and older.
Wimpat ® in the form of a solution for infusion is prescribed in cases where the drug is temporarily impossible to take inside.
Pregnancy and lactation
Clinical data on the use of lacosamide during pregnancy are not available. Lacosamide should not be used during pregnancy, unless the benefit to the mother clearly outweighs the potential risk to the fetus.
If a woman is planning a pregnancy, then it is necessary to carefully weigh the appropriateness of using this drug.
In experimental studies, no teratogenic effects were recorded, but embryotoxicity was noted when used in high (toxic) doses.
Data on the allocation of lacosamide with human breast milk are not available. In experimental studies, the excretion of lacosamide with breast milk was noted.
During treatment with lacosamide, breast-feeding should be discontinued.
Use in children
Contraindicated in children and adolescents under 16 years of age.
Wimpat is contraindicated in children under 16 years of age, pregnant and lactation
Contraindications
- AV block II or III degree;
- age up to 16 years;
- hereditary fructose intolerance, sucrose-isomaltase deficiency, glucose-galactose malabsorption (because fructose is part of the syrup);
- phenylketonuria (since aspartame is part of the syrup);
- hypersensitivity to the components of the drug, including to soy (included in the tablet shell), as well as to peanuts.
With caution, the drug should be used in patients with severe renal failure (CC ≤ 30 ml / min), with impaired conduction, heart failure, and a history of myocardial infarction. Particular 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 a prolongation of the PR interval.
Use for impaired liver function
When taken orally and with iv, in patients with mild to moderate impaired liver function, dose adjustment is not required. Such patients should be titrated with caution, given that impaired liver function is often associated with impaired renal function. The pharmacokinetics of lacosamide in patients with severe hepatic insufficiency has not been studied.
Use for impaired renal function
Ingestion and with iv administration to patients with mild to moderate impaired renal function (CC> 30 ml / min) dose adjustment is not required. In patients with severe renal failure (CC
Use in children
Contraindicated in children and adolescents under 16 years of age.
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 decrease. 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, as a result of which the development of such clinical conditions as AV block, fainting, and bradycardia is possible.
Adverse reactions observed in more than 1% of patients in clinical trials are listed below. Determination of the frequency of adverse reactions: very often (≥1 / 10); often (from ≥1 / 100 to
From the side of the central nervous system: very often - dizziness, headache; often - depression, irritability, impaired balance, impaired coordination of movements, impaired memory, impaired attention, cognitive impairment, hypesthesia, drowsiness, confusion, tremor, nystagmus, dysarthria.
From the sensory organs: 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.
From the musculoskeletal system: often - muscle cramps.
Other: often - gait disturbance, asthenia, fatigue, falls, increased risk of injury (due to impaired coordination of movements and dizziness).
Interaction
Research results indicate a low likelihood of lacosamide interacting with other drugs.
In preclinical studies, synergism or additive anticonvulsant effect was observed in combination with levetiracetam, carbamazepine, phenytoin, valproic acid, lamotrigine, topiramate, gabapentin.
Lacosamide should be used carefully in combination with drugs that cause a prolongation of the PR interval (for example, carbamazepine, lamotrigine, pregabalin) and class I antiarrhythmic drugs. However, in clinical studies, there was no additional lengthening of the PR interval 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, caution should be exercised when prescribing such drugs or discontinuing them.
Lacosamide at any therapeutic dose has no effect on C ss in plasma anticonvulsants, including levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine, phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam and zonisamide.
Carbamazepine and valproic acid did not affect the plasma concentration of lacosamide.
Concomitant therapy with anticonvulsants inducing enzymes (carbamazepine, phenytoin, phenobarbital in various doses) reduced the total systemic exposure of lacosamide by 25%.
No evidence of a significant interaction between lacosamide and oral contraceptives, ethinyl estradiol and levonorgestrel. Lacosamide does not affect the concentration of progesterone.
Lacosamide does not affect the pharmacokinetics of digoxin.
No clinically significant interaction of lacosamide and metformin was detected.
There is 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 have clinical significance. When taking a single dose, lacosamide did not affect the pharmacokinetics of omeprazole. The effect of other isoenzymes of cytochrome P450 and other enzymes on the metabolism of lacosamide has not been accurately established. Lacosamide is not a substrate or an 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.
How to take, course of administration and dosage
For oral administration
The daily dose is divided into 2 doses - morning and evening, regardless of the meal time.
The recommended starting dose is 50 mg 2 times / day. After 1 week, the dose is increased to 100 mg 2 times / day. Given 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 cancel Wimpat ® gradually, reducing the dose by 200 mg per week.
For iv administration
In / in is administered for 15-60 minutes 2 times / day.
The recommended starting dose is 50 mg 2 times / day. After 1 week, the dose is increased to 100 mg 2 times / day. Given 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 cancel Wimpat ® gradually (reducing the dose by 200 mg per week).
The solution can be administered without further dilution or diluted.
There is experience in using an infusion solution lasting up to 5 days. You should switch to taking the drug inside as soon as possible.
Treatment with Wimpat ® can be started both by taking the tablets inside, and with the on / in the introduction of a solution for infusion.
If necessary, you can replace the intake of IV tablets without repeated titration of the dose and vice versa. In this case, the daily dose and frequency of administration (2 times / day) should not be changed.
When taken orally and with iv, in patients with mild to moderate impaired renal function (CC> 30 ml / min), dose adjustment is not required. In patients with severe renal failure (CC ≤ 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%. It is recommended that patients on hemodialysis receive an additional 50% of a single dose immediately after the procedure. Treatment of patients with severe renal failure should be carried out with caution, because clinical experience with the use of the drug in such patients is small, and the accumulation of a metabolite that does not have a known pharmacological activity is possible. All patients with impaired renal function should be titrated with caution.
When taken orally and with iv, in patients with mild to moderate impaired liver function, dose adjustment is not required. Such patients should be titrated with caution, given that impaired liver function is often associated with impaired renal function. The pharmacokinetics of lacosamide in patients with severe hepatic insufficiency has not been studied.
When administered orally and with iv administration to elderly patients, a dose reduction is not required. Experience with lacosamide in elderly patients with epilepsy is limited. In older people, 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 evidence of an overdose of lacosamide is limited.
Symptoms: after taking the drug at a dose of 1200 mg / day - mainly dizziness and nausea, which disappeared after a dose reduction. During clinical trials, a single dose of 12 g of lacosamide was recorded, which was taken along with toxic doses of other antiepileptic drugs. The patient fell into a coma, but then fully recovered without consequences.
Treatment: the antidote of lacosamide does not exist; conduct symptomatic therapy; if necessary, hemodialysis is possible.
Special instructions
Lacosamide treatment may be accompanied by dizziness, potentially leading to injuries and falls. In this regard, patients should be careful.
Analysis of clinical trials of anticonvulsants indicates a slight increase in the risk of suicidal thoughts and suicidal behavior. The mechanism for increasing 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 of the existing risk and the need to consult a specialist in case of suicidal behavior. Patients receiving lacosamide treatment should be closely monitored and warned of the need for specialist advice in the event of suicidal thoughts.
Given the possibility of prolonging the PR interval during therapy with Wimpat ® , patients are advised to periodically monitor the ECG.
The syrup contains excipients sodium propyl parahydroxybenzoate (E217) and sodium methyl parahydroxybenzoate (E219), which can cause allergic reactions (including delayed type). The 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 sodium-restricted diet.
Pediatric Use
Lacosamide is not recommended for 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 the ability to drive vehicles and control mechanisms
The drug may affect the ability to drive a car or use sophisticated equipment. Treatment with this drug may be accompanied by dizziness or blurred vision. Accordingly, patients are not recommended to drive a car or operate sophisticated equipment.
Release form
Pills
