Briviak tablets 25 mg 56 pcs

Pharmacotherapeutic group:

antiepileptic drug
CODE ATX: N03AX23
Pharmacological properties
Pharmacodynamics
Brivaratsetam has a high and selective affinity for the synaptic vesicle protein 2A (SV2A) in the brain – transmembrane glycoprotein contained in neurons and endocrine cells at the presynaptic level. Although the exact role of this protein is currently unknown, it has been shown that it modulates neurotransmitter exocytosis.
Binding of glycoprotein synaptic vesicle 2A (SV2A) appears main mechanism anticonvulsant effect brivaratsetama.
The efficacy and safety of clinical application
Efficiency brivaratsetama as adjunctive therapy of partial seizures (CAP) was established in three randomized, double-blind, placebo-controlled, multicenter studies of the drug in a fixed dose in patients aged 16 years and older.
The study drug was prepared in 1558 patients, of which 1099 patients were treated brivaratsetam at a dose of 5 to 200 mg / day. In all studies was the original 8-week period, after which followed a 12-week treatment period, without increasing the dose. The study included patients with uncontrolled presence of CAP in patients receiving concomitant 1 or 2 antiepileptic drugs (AEDs).
During treatment, patients were included in which during the starting period occurred at least 8 SRP. Primary endpoints in the study were 3 phase percentage reduction SRP frequency compared with placebo and the proportion of patients achieving a reduction in memory bandwidth frequency not less than 50% relative to the initial level. At study entry, patients frequently take such probes as carbamazepine (40.6%). lamotrigine (25.2%), valproate (20.5%), oxcarbazepine (16.0%), topiramate (13.5%). phenytoin (10.2%) and levetiracetam (9.8%). When you turn in all three studies the median frequency of seizures per 28 days was equal to 9. The duration of epilepsy was on average about 23 years.
brivaratsetama efficacy has been demonstrated as an adjunctive therapy in CAP patients aged 16 years or older at doses ranging from 50 mg / day to 200 mg / day.
In clinical studies, reduction in the incidence of seizures compared to the placebo group was more pronounced when applying brivaratsetama 100 mg / day, 50 mg / day. Except for a small dose-dependent increase in cases of drowsiness and fatigue, application brivaratsetama in doses of 50 mg / day and 100 mg / day was characterized by a comparable safety, including in respect of adverse effects on the part of the central nervous system and on the background of long-term therapy.
According to the combined analysis of patients the percentage in which the frequency of the CAP decreased by at least 50% relative to baseline for patients receiving brivaratsetama at doses of 50 mg / day, 100 mg / day and 200 mg / day, was, respectively, 34.2%, 39 , 5% and 37.8% compared with 20.3% in the placebo group (in this analysis did not include patients taking levetiracetam).
In the pooled analysis of these three basic studies revealed no differences efficiency (defined as a reduction in memory bandwidth frequency by 50% relative to baseline) brivaratsetama doses ranging from 50 mg / day to 200 mg / day in combination with inducing or non-inducing AEDs.
During the treatment period, which was 12 weeks, freedom from attacks was achieved in 2.5% (4/161) 5.1% (17/332) and 4.0% (10/249) of the patients treated in brivaratsetam doses of 50 mg / day, 100 mg / day and 200 mg / day, respectively, compared to the placebo group where the figure was 0.5% (2/418). Reducing the frequency of seizures in 28 days was observed in patients suffering from baseline 1C type seizures (secondary generalized tonic-clonic seizures), taking brivaratsetam in doses of 50 mg / day, 100 mg / day and 200 mg / day, 66.6% (n = 62), 61.2% (n = 100) and 82.1% (n = 75), respectively, compared to placebo – 33.3% (n = 115)
.
brivaratsetama effectiveness as monotherapy has not been confirmed. Brivaratsetam not recommended for use as monotherapy.
Levetiracetam therapy
In two randomized, placebo-controlled clinical studies levetiracetam concomitant AEDs was approximately 20% of patients. Although the number of such patients is limited, it was noted that the benefits brivaratsetama compared with placebo have not seen, which could be due to competitive binding with glycoprotein SV2A. Additional problems in the safety and tolerability of this therapy was also not revealed.
In the third study showed brivaratsetama advantage in doses of 100 mg / day and 200 mg / day compared with placebo in patients previously treated with levetiracetam. In this subgroup of patients brivaratsetama lower efficiency compared to patients not previously treated levetiracetam, could be a consequence of receiving a larger number of probes, and a history of greater initial frequency of seizures.
Use in elderly patients (aged 65 years and older)
The three basic double-blind, placebo-controlled studies were vklyucheny38 patients aged 65 to 80 years. Efficiency brivaratsetama in elderly patients was comparable to that of those of younger people, although the data are limited.
Use in children
Efficacy and tolerability of brivaratsetama in children under the age of 16 years have not been established (see. Section “Pharmacokinetics»).
Open extended research
After completion of randomized trials of 81.7% of patients were included in the long open phase brivaratsetama application. After 6 months of randomized study inclusion in absence seizures was observed in 5.3% (n = 1500) of patients after 12 months – in 4.6% (n = 1188) and patients after 24 months – 3.7% (n = 847) treated brivaratsetam. However, given the fact that a significant proportion of patients (26%) prematurely discontinued the extended studies due to lack of efficacy can not be excluded that the analysis of the data unrepresentative sample was included as the remaining patients responded better to therapy than prematurely eliminated .
Preclinical safety data
The pharmacological safety studies revealed a predominant influence on the CNS (mostly transient CNS depression and decrease of spontaneous locomotor activity) is observed with the administration of the drug in doses significantly (more than 50 times) than the pharmacologically active dose brivaratsetama 2 mg / kg.

Brivaratsetam no effect on learning and memory.
There was no evidence of pathological changes in the liver of rats and monkeys with chronic use brivaratsetama at doses much (from 5 to 42 times) than the therapeutic dose of 200 mg / day. They were registered signs of CNS lesions which over time weakened (depression, loss of balance, discoordination) in monkeys when applying brivaratsetama at doses 64 times higher than clinical Cmax dogs application brivaratsetama led to the development of changes in the liver, primarily to porphyria in dosages that will provide exposure (determined by the area under concentration-time curve, AUC), close to the average exposure in humans at a dose of 200 mg / day. However, toxicological data on the structurally close brivaratsetamu and components show that the development of changes in the liver of dogs going on mechanisms not peculiar to humans.
In genotoxicity studies showed no mutagenic or clastogenic activity. carcinogenicity studies in rats have not found oncogenic potential, while the increased incidence of hepatocellular tumors in male mice was regarded as caused negenotoksichnym mechanism of action pertaining to the induction of hepatic enzymes fenobarbitalopodobnoy that is a known phenomenon specific to the rodent.
Brivaratsetam no effect on fertility in males and females revealed no teratogenic potential in experiments in rats and rabbits. Embryotoxicity is marked in the application brivaratsetama pregnant female rabbits at a dose toxic to females at which the exposition is 8 times higher than the clinical exposure at the recommended maximum dose. Rats brivaratsetam rapidly cross the placenta and are excreted in the milk of lactating rats at concentrations close to the maternal plasma concentration.
Studies in rats showed no potential for the development of drug dependence.
Studies in immature animals
In immature rats with an exposure brivaratsetama in 6-15 times the clinical exposure at a maximum recommended dose, it was observed adverse effect on the development of processes (mortality, clinical signs, weight loss and decreased brain weight). There were no adverse effects on the central nervous system function as well as neuropathological and histopathological changes in the brain. In immature dogs when applying brivaratsetama in a dose that provides exposure to 6 times higher than the therapeutic level, the changes were similar to changes in adult animals.
There were no side effects, taking into account the standard criteria for the assessment of development and maturation.
Pharmacokinetics
Characterized Brivaratsetam linear and independent of the duration of therapy pharmacokinetics, low intra- and interindividual variability and complete absorption, a very small degree of binding to plasma proteins, excretion by the kidneys after extensive biotransformation and presence pharmacologically inactive metabolites.
suction
Brivaratsetam rapidly and completely absorbed after oral administration, and its sostavlet absolute bioavailability of approximately 100%. The median time to reach maximum concentration (Tmax) when the pill is fasting 1 hr (scatter Tmax values ​​of 0.25 to 3 hours).
Simultaneous reception brivaratsetama food with high fat slows the rate of absorption (median Tmax for 3 hours) and reduces the maximum drug concentration in plasma by 37%, whereas the extent of absorption remains unchanged.
distribution
Brivaratsetam little bound to plasma proteins (< 20%). The volume of distribution of 0.5 l / kg, which is close in value to the total fluid volume in the body. Due to the lipophilic (Log P) brivaratsetam well penetrates through cell membranes.
metabolism
Brivaratsetam metabolized primarily by hydrolysis of the amide component to form the corresponding carboxylic acid (approximately 60% of the dose), a second – by the hydroxylation propyl side chain (approximately 30% of the dose). Hydrolysis of the amide component to form a carboxylic acid (34% of the dose, renal excretion) mediated hepatic and extrahepatic amidase. In vitro hydroxylation brivaratsetama mediated primarily isoenzyme of cytochrome P450 CYP2C19. Both metabolites during further conversion hydroxylated acid form. In vivo in humans with isoenzyme CYP2C19 inactive due to mutation, hydroxy metabolite formation is reduced by 10 times, while the concentration brivaratsetama increased to 22% or 42% in subjects with one or both mutated alleles. These three metabolites lack pharmacological activity.
Withdrawal
Brivaratsetam primarily metabolized and excreted by the kidneys. More than 95% of the dose, including the metabolites excreted by the kidneys within 72 hours after administration. Less than 1% of the dose is excreted in the intestine and less than 10% of the dose is excreted unchanged by the kidneys. The terminal half-life brivaratsetama (T1 / 2) is about 9 hours. Total plasma clearance brivaratsetama patients is 3.6 l / h
Linearity
Pharmacokinetics proportional to the dose in the range from 10 to at least 600 mg.
Drug interactions
Brivaratsetam displayed in several ways, including renal excretion is not mediated by cytochrome P450 isozymes system mediated hydrolysis and isozymes of the cytochrome P450 oxidation. In studies in vitro demonstrated that brivaratsetam not a substrate of the human glycoprotein (P-gp), human protein responsible for multidrug resistance (MRP1 and MRP2) and probably polypeptides vectors organic anions 1B1 (OATR1V1) and (OATR1VZ).
Experiments in vitro showed that biotransformation brivaratsetama substantially independent of isozymes CYP inhibitors (e.g., CYP1 A, 2S8, 2S9, 2D6 and ZA4). In studies in vitro demonstrated that brivaratsetam not an inhibitor of isozyme CYP1A2, 2A6, 2B6, 2S8, 2S9, 2D6, ZA4 or transporter P-gp, BCRP, BSEP MRP2, MATE-K MATE-1 OATR1V1, OATR1VZ, OAT1 and CAP at concentrations comparable to those used in the clinic. Also, in in vitro studies brivaratsetam did not induce CYP1A2 isoenzyme.
Pharmacokinetics in special patient groups
Elderly (65 years and older)
In a study in elderly patients (age 65-79 years, with creatinine clearance 53-98 ml / min / 1.73 m), brivaratsetam receiving 400 mg / day for two steps, the period of half-life was 7.9 hours and 9 3 hours in groups of 65-75 years and above 75 years of age, respectively. In equilibrium, the clearance brivaratsetama in elderly patients was similar (0.76 mL / min / kg) for clearance in healthy young men (0.83 mL / min / kg).
In patients with impaired renal function
In patients with severe renal failure (creatinine clearance < 30 ml / min / 1.73 m2, without the need for hemodialysis) brivaratsetama plasma concentration (determined by AUC) was moderately enhanced (21%) compared with that of healthy volunteers. In this case, the concentration of acid, hydroxyl and hydroxy acid metabolites were increased to 3, 4 and 21 times, respectively. Renal clearance of said inactive metabolites decreased by 10 times. According to the results of preclinical safety hydroxy acid metabolites did not cause concern.
Brivaratsetam not studied in patients on hemodialysis.
In patients with impaired liver function
Pharmacokinetic study in patients with hepatic cirrhosis (A, B, C in Child-Pugh) showed a comparable increase in exposure brivaratsetama, regardless of the degree of disease severity (50%, 57% and 59%) compared with the control group of healthy volunteers.

Children
In a pharmacokinetic study in 99 children aged 1 month to 16 years who received brivaratsetama into solution brivaratsetama plasma concentration is proportional to the dose in all age groups. These population pharmacokinetic modeling showed that a dose of 2.0 mg / kg twice a day results in the same average equilibrium concentration in plasma as a dose of 100 mg twice a day in adults.
Influence
weight
It showed a reduction in the equilibrium brivaratsetama concentration in blood plasma by 40% in patients with a body weight ranging from 46 to 115 kg. However, such a difference in the pharmacokinetics of brivaratsetama regarded as clinically insignificant.
Influence of gender
No clinically significant differences in the pharmacokinetics of brivaratsetama patients of different sexes is not revealed.
Influence
race
Race (Caucasian, Mongoloid) had no significant effect on the pharmacokinetic parameters brivaratsetama, according to the results of population pharmacokinetic modeling in patients with epilepsy. The number of patients of other ethnic origin has been limited.
Pharmacokinetic / pharmacodynamic relationship
Meaning brivaratsetama plasma concentration is 50% of the maximally effective concentration (EC50) corresponds to 0.57 mg / l. This plasma concentration is somewhat higher than the median value brivaratsetama exposure after dosing 50 mg / day. Further reduction in the incidence of seizures observed with increasing dose up to 100 mg / day, efficiency reaches a plateau while taking the drug at a dose of 200 mg / day.

Active substance:
Brivaracetam

Manufacturer

YUSB Pharma SA, Belgium

Prescribing

For adults on prescription

Composition

Active substance: brivaratsetam 25.00 mg;

Other ingredients: croscarmellose sodium 5.00 mg lactose monohydrate 48.50 mg, 6.75 Betadeks mg anhydrous lactose 48.25 mg magnesium stearate 1.50 mg film coating Opadry II 85F275014 gray 6.75 mg (polyvinyl alcohol , talc, polyethylene glycol 3350 / macrogol 3350, silica, iron oxide colorant titanium yellow, iron oxide black dye).

Indications

Epilepsy
Briviak indicated as adjunctive therapy in the treatment of partial seizures with secondary generalization or without in adults and adolescents from 16 years of age with epilepsy.

Contraindications

• Hypersensitivity to the active substance or other pyrrolidone derivatives, and any of the support components, listed in the “Composition».


• Children under 16 years (in the absence of clinical data).


• rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption.


• end-stage renal failure requiring hemodialysis (in the absence of clinical data).

PRECAUTIONS FOR USE

In patients with the presence of:

• suicidal thoughts and suicide attempts
• liver dysfunction (see. Sections “Dosage and administration” and “Special instructions»).

Side effects

Rezyume safety profile
Safety Briviak preparation was evaluated in 2388 patients, of whom 1740 poluchalibrivaratsetam for > 6 months, the patient’s 1363 – > 12 months, 923- > 24 months and 569 – > 60 months (5 years).
Most often (> 10%) during the treatment brivaratsetamom noted somnolence (14.3%), and dizziness (11.0%). These adverse drug reactions (ADRs) were usually mild or moderate severity. The incidence of fatigue and sleepiness (8.2%) increased with increasing dose. Types of adverse reactions was noted during the first 7 days of treatment were similar to those recorded during the entire treatment period.
The frequency of early termination of therapy due to development of ADRs was 3.5%, 3.4% and 4.0% in patients randomized to receive brivaratsetama at doses of 50 mg / day,
100 mg / day and 200 mg / day, respectively; that in the placebo group it was 1.7%. The most common ADRs, leading to the early abolition of brivaratsetama, were dizziness (0.8%), and seizures (0,8%).
ADRs are presented in accordance with a lesion of organs and organ systems (MedDRA) and classified by the frequency of occurrence: very often (> 1/10); often (> 1/100, but < 1/10) and rarely (> 1/1000, but < 1/100).
Infectious and parasitic diseases
Often: Flu
Blood disorders and lymphatic system
Infrequently:
neutropenia
Violations by the metabolism and nutrition
Common: Decrease in appetite
Violations
psyche
Often, depression, anxiety, insomnia, irritability Uncommon: suicidal ideation, psychotic disorder, aggression, agitation
Disorders of the nervous system
Very common: dizziness, somnolence Common: convulsions, vertigo
Violations of the respiratory system, thorax and mediastinum
Common: upper respiratory tract infection, cough
Violations by the gastrointestinal tract
Common: nausea, vomiting, constipation
General disorders and administration site in
Common: fatigue
Description of individual
NLR
Neutropenia was observed in 0.5% (6 of 1099) of patients treated brivaratsetam, and 0% (0 out of 459) of patients receiving placebo. In 4 of these patients had reduced the number of neutrophils at baseline, and it was noted further decline during treatment brivaratsetamom. None of the 6 cases of neutropenia was not serious, did not require special treatment, he did not lead to discontinuation brivaratsetama and was not accompanied by infectious complications.
Suicidal intent marked in 0.3% (3 of 1099) of patients treated brivaratsetam, and 0.7% (3 of 459) of patients receiving placebo. Within the framework of short-term clinical trials of brivaratsetama in patients with epilepsy cases of suicide and suicide attempts are not mentioned, however, both of these phenomena are recorded in the extended phase of the open investigation.
Open extended research
The safety profile brivaratsetama in the short-term, placebo-controlled studies was comparable to its safety profile in patients who continued to use the drug in the long-term open-phases for up to 8 years.
Use in children
Data on the safety brivaratsetama within the open-label studies in children aged 1 month to < 16 years is limited. In total, 152 children (1 month to < 16 years) received brivaratsetam within pharmacokinetic studies and follow-up. According to the limited data available the most common adverse events regarded physician-investigator as related to drug were somnolence (10%), poor appetite (8%), fatigue (5%) and weight loss (5%). The safety profile in children was comparable to brivaratsetama safety profile in adults. Data on the impact on the development of the nervous system are absent. There is currently no information on the results of the clinical use of the drug in infants.
Use in elderly
Of the 130 elderly patients included in the clinical studies brivaratsetama 2-3 phases (44 with epilepsy), 100 patients were aged 65-74 years, and 30 patients – aged 75 – 84 years. brivaratsetama safety profile was similar in elderly and younger adult patients.

How to accept, acceptance rate and dosage

Inside, without chewing, drinking water, regardless of the meal (see. The section “Pharmacological properties”).

The recommended starting dose is 50 mg / day or YuOmg / day, decision of the treating physician, based on the desired effect and anticonvulsant and potential side effects. The daily dose is divided equally into two doses, morning and evening. Depending on induvidualnogo patient response and tolerability, the dose can bytizmenena between 50 mg / day to 200 mg / day, in which brivaratsetam effective as a concomitant therapy SRP. Initial dose titration is not required to effectively account portability brivaratsetamom therapy.

In the case of skip one or more missed doses it is recommended to take a dose of the drug as soon as possible; take the next dose at the usual time in the morning or in the evening. Restores the missed dose reduction to avoid brivaratsetama plasma concentrations below the effective level and to prevent the recurrence of seizures.

removal of the drug

recommended to cancel the drug gradually reducing the dose to 50 mg / day of a week, if necessary discontinue brivaratsetamom. After one week of dosing, 50 mg / day is recommended to take brivaratsetam last week at a dose of 20 mg / day.

Features of the application in selected groups of patients

Elderly (65 years and older)

No dose adjustment in elderly patients is not required (see. Section “Pharmacokinetics”). The experience of use in patients aged 65 years and older is limited.

Renal function

Dose adjustment for patients with impaired renal function is not required (see. The section “Pharmacokinetics”). Brivaratsetam is not recommended in patients with end-stage renal failure requiring dialysis, due to the lack of clinical data.

Abnormal liver function

In patients with chronic liver disease exposure brivaratsetama increased. It should begin with a dose of 50 mg / day. The recommended maximum daily dose for all stages of liver failure is 150 mg, divided in two stages (see. The section “Pharmacokinetics).”

Children

The safety and efficacy brivaratsetama in infants and children under the age of 16 years have not been established. The received data thus far refer to “Side effect” and “Pharmacological Properties”.

Storage conditions

Store at a temperature not higher than 30 ° C. Keep out of the reach of children.

Active substance

Brivaracetam

Interaction

Drug interactions studies were conducted only in adults.
Pharmacodynamic interactions
Interactions with levetiracetam
In a limited number of clinical studies have not indicated brivaratsetama benefits compared with placebo in patients concurrently treated with levetiracetam. Additional effect on safety or tolerability was also not detected (see section “Pharmacodynamic»).
Interaction with
ethanol
In a study of the pharmacokinetic and pharmacodynamic interaction between brivaratsetamom (for receiving a single dose of 200 mg) and ethanol (if continuous infusion at a concentration of 0.6 g / l) in healthy volunteers the pharmacokinetic interaction was noted. However, the effect of alcohol on psychomotor performance, attention and memory has doubled, while the use brivaratsetamom. It is not recommended to drink alcohol on the background brivaratsetamom therapy.
Pharmacokinetic interaction
The influence of other drugs on the pharmacokinetics of brivaratsetama
It characterized Brivaratsetam low potential to participate in the drug-drug interactions in vitro. The main route of biotransformation brivaratsetama is CYP-independent hydrolysis. The second path includes biotransformation hydroxylation mediated isoenzyme CYP2C19 (see. The section “Pharmacokinetics”). Brivaratsetama may increase the concentration of its combination with potent inhibitors of isoenzyme CYP2C19 (fluconazole, fluvoxamine), but the risk of clinically significant interactions mediated by isoenzyme of CYP2C19, considered to be low.
Rifaipitsin
Simultaneous application in healthy volunteers with potent inducer enzyme rifampicin (600 mg / day for five days) was associated with decreased brivaratsetama exposure values ​​by 45%. It is necessary to adjust the dose in patients brivaratsetama beginning or ending treatment with rifampicin.
AEDs that are potent inducers of enzymes
Concentration brivaratsetama reduced by combining it with the probe, which are potent inducers of enzymes in the blood plasma (carbamazepine, phenobarbital, phenytoin), but the correction dose regimens in this situation is not required.
Other inducers of enzymes
Other potent inducers of enzymes (such as St. John’s wort) may also reduce the systemic exposure brivaratsetama. Therefore, care should be taken at the beginning and at the end receive Hypericum perforatum during treatment brivaratsetamom.
Brivaratsetama influence on other medications
Brivaratsetam in doses from 50 to 150 mg / day did not affect the AUC of midazolam (metabolizable isoenzyme CYP3A4). The risk of developing clinically significant interactions mediated by isoenzyme of CYP3A4, is considered low.
In vitro studies have shown that CYP450 isoenzymes brivaratsetam inhibited to a small extent, or not inhibiting at all, except for CYP2C19.
Brivaratsetam can increase the concentration in the blood plasma of drugs metabolized with isoenzyme CYP2C19 (e.g., lansoprazole, omeprazole, diazepam). In experiments in vitro brivaratsetam not induced isozyme CYP1A1 / 2, but induced isozymes CYP3A4, and CYP2B6. There was no induction of isoenzyme CYP3A4 in vivo (see. Midazolam above). Effect on isoenzyme CYP2B6 was not studied in vivo, brivaratsetam can reduce the concentration of drugs in blood plasma, with the participation of metabolizable isoenzyme CYP2B6 (e.g., efavirenz).
The in vitro drug-drug interaction studies to evaluate the potential inhibitory effect on the drug transporters, it was concluded the absence of clinically significant effects, except for the effects on the organic anion transporter 3 (OATZ). Concentration brivaratsetama in vitro, which provides 50% of the maximum inhibitory effect OATZ was 42-fold higher than the Cmax when receiving the maximum therapeutic dose. Brivaratsetam a dose of 200 mg / day may increase the plasma concentrations of drugs carried OATZ.

antiepileptics
Potential interactions between brivaratsetamom (in doses from 50 to 200 mg / day) and the other probe was evaluated under the combined analysis of plasma concentration values ​​preparation obtained in all trials 2 and 3 phases (including a population pharmacokinetic analysis of placebo-controlled trials 2 and 3 phase), and special studies of drug interactions to the following probe: karbamazemin, lamotrigine. phenytoin and topiramate.
carbamazepine
Brivaratsetam represents moderate epoxide reversible inhibitor that enhances the concentration of epoxide carbamazepine (carbamazepine active metabolite) in blood. In controlled studies, the plasma concentration of epoxide carbamazepine increased on average by 37%, 62% and 98% (low variability) amid simultaneous application brivaratsetama at doses of 50 mg / day, 100 mg / day or 200 mg / day, respectively. the safety profile did not change. Not detected additional effect brivaratsetama valproate and carbamazepine epoxide in the AUC.
Oral contraceptives
Combined application brivaratsetama (100 mg / day), with oral contraceptive containing ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg) had no effect on the pharmacokinetic parameters of any of the components of the combination. In simultaneous reception brivaratsetama dose of 400 mg / day (dose exceeding the maximum recommended daily dose of 2 times) with an oral contraceptive containing ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg) decreased AUC values ​​of estrogen and progestin in 27% and 23%, respectively, which did not affect the degree of suppression of ovulation. Not registered and change profiles of concentration vs. time for endogenous estradiol markers, progesterone, luteinizing hormone, follicle-stimulating hormone binding globulin and sex hormone binding.

Special conditions

Cancel
drug
recommended to cancel the drug gradually reducing the dose to 50 mg / day of a week, if necessary discontinue brivaratsetamom. After one week of receiving a dose of 50 mg / day is recommended to take brivaratsetam last week at a dose of 20 mg / day.
Suicidal ideation and suicide attempts
Suicidal ideation and suicide attempts were reported in patients treated with AEDs, including brivaratsetam, for various reasons. A meta-analysis of randomized placebo-controlled trials of AEDs has also shown a small increased risk of suicidal ideation and attempts.
The mechanism of occurrence of suicide risk is unknown, and there is a possibility of increased risk when using brivaratsetama.
It is necessary to control the signs of suicidal ideation and attempts in patients in a timely manner to start appropriate treatment. Patients (and caregivers) should be informed of the need to seek immediate medical attention if you experience suicidal ideation or attempts.
Impaired function of the liver
Clinical data on the use brivaratsetama in patients with hepatic insufficiency are limited. Recommended dose correction drug in patients with impaired liver function (see. The section “Method of administration and dose»).
Effects on ability to driving and other mechanisms
Brivaratsetam mild or moderate influence on the ability to drive vehicles and other mechanisms.
Due to differences in individual sensitivity to the drug in some patients may develop drowsiness, dizziness and other effects to the central nervous system. Patients are advised not to drive a car or to operate other potentially hazardous machinery until brivaratsetama impact on their ability to perform such activities will not be clear to them.

Pregnancy and lactation

pregnancy
Risk due to epilepsy and antiepileptic drugs taking
Among babies born to women treated with antiepileptic drugs, the number of congenital malformations is 2-3 times higher than the value of about 3%, which is characteristic for the population as a whole. Simultaneous therapy multiple antiepileptic drugs is associated with a higher risk of congenital malformations, but the contribution of each product and / or the disease itself is not separately evaluated.
Discontinuation of antiepileptic therapy may lead to an aggravation of the disease, which may prove dangerous to both mother and fetus.
Risk due
brivaratsetamom
brivaratsetama studies in animals did not reveal any teratogenic potential.
These applications brivaratsetama in pregnant women is limited. In clinical studies, the application brivaratsetama as adjunctive therapy in combination with carbamazepine, marked dose-dependent increase in the concentration of the active metabolite of carbamazepine – epoxide carbamazepine (see “Interaction with other drugs” section.). Data to determine the clinical relevance of this effect in pregnant women is not enough.
There are no data on the penetration brivaratsetama the placental barrier in humans. Rats brivaratsetam easily crosses the placenta. The potential risk for humans is unknown.
Brivaratsetam should not be used during pregnancy unless the clinical need when the benefit to the mother clearly exceeds the potential risk to the fetus.
Brivaratsetama discontinuation may cause worsening of the disease, which can be dangerous for both mother and fetus.
Breastfeeding
It is unknown whether brivaratsetam excreted in human breast milk. In lactating rats brivaratsetam excreted in milk. The decision to terminate breast-feeding or receiving brivaratsetama adopted on the basis of assessing the need for therapy for the mother. While admission brivaratsetama and carbamazepine may increase the amount of epoxide of carbamazepine. excreted into breast milk. Data to assess the clinical significance is not enough.
Fertilnost
Data on the effect on fertility of man brivaratsetama not. In rats receiving brivaratsetama no effect on fertility.
Women with preserved childbearing potential
Before the appointment brivaratsetama doctor should discuss family planning and contraceptive measures for women whose reproductive function preserved. When planning a pregnancy, the woman question of the continuation reception brivaratsetama should be reconsidered.

Overdose

Brivaratsetama clinical experience of overdose in humans is limited. In healthy volunteers who received single brivaratsetam dose of 1400 mg, marked drowsiness and dizziness.
Specific antidote for brivaratsetama not. In case of overdose, general supportive therapy is conducted. As with urine output less than 10% brivaratsetama unlikely that hemodialysis will greatly increase the clearance brivaratsetama (see. The section “Pharmacological properties”).