Briviak (BRIVIAK)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceBrivaracetamBrivaracetam
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  • Briviak
    pills inwards 
    YUSB Farma S.A.     Belgium
    • Dosage form: & nbspfilm coated tablets
    Composition:

    1 tablet of 10 mg contains:

    Active substance: Brivaracetam 10.00 mg;

    Excipients: croscarmellose sodium 4.00 mg, lactose monohydrate 45.0 mg, Betadec 2.70 mg, anhydrous anhydrous 45.10 mg, magnesium stearate 1.20 mg, film sheath Opadrai II 85F18422 white 5.40 mg (polyvinyl alcohol, talc, polyethylene glycol 3350 / macrogol 3350, titanium dioxide).

    1 tablet of 25 mg contains:

    Active substance: Brivaracetam 25.00 mg;

    Excipients: croscarmellose sodium 5.00 mg, lactose monohydrate 48.50 mg, Betadec 6.75 mg, lactose anhydrous 48.25 mg, magnesium stearate 1.50 mg, film coat Opadrai II 85F275014 gray 6.75 mg (polyvinyl alcohol, talc, polyethylene glycol 3350 / macrogol 3350, titanium dioxide, iron dye oxide yellow, iron oxide dye black).

    1 tablet of 50 mg contains:

    Active substance: Brivaracetam 50.00 mg;

    Excipients: croscarmellose sodium 10.00 mg, lactose monohydrate 97.0 mg, Betadec 13.50 mg, lactose anhydrous 96.50 mg, magnesium stearate 3.00 mg, film coat Opadrai II 85F38197 yellow 10.80 mg (polyvinyl alcohol, talc, polyethylene glycol 3350 / macrogol 3350, titanium dioxide, iron dye oxide yellow, iron oxide dye red).

    1 tablet 75 mg contains:

    Active substance: Brivaracetam 75.00 mg;

    Excipients: Croscarmellose sodium 15.00 mg, lactose monohydrate 145,50 mg, Betadec 20,25 mg, lactose anhydrous 144,75 mg, magnesium stearate 4.50 mg, film shell Opadrai II 85F200021 purple 14.18 mg (polyvinyl alcohol, talc, polyethylene glycol 3350 / macrogol 3350, titanium dioxide, iron oxide yellow oxide, iron oxide red dye, iron oxide oxide black).

    1 tablet of 100 mg contains:

    Active substance: Brivaracetam 100.00 mg;

    Excipients: Croscarmellose sodium 20.00 mg, lactose monohydrate 45.0 mg, Betadec 27.00 mg, lactose anhydrous 193.00 mg, magnesium stearate 6.00 mg, film coat Opadrai II 85F270000 tan 16.20 mg (polyvinyl alcohol, talc, polyethylene glycol 3350 / macrogol 3350, titanium dioxide, iron dye oxide yellow, iron oxide dye black).

    Description:

    Tablets 10 mg

    Round biconvex tablets covered with a film shell, from white to almost white, engraved with "u10" on one side.

    Tablets 25 mg

    Oval biconvex tablets covered with a film shell, gray, engraved "u25" on one side.

    50 mg tablets

    Oval, biconvex tablets covered with a film membrane, yellow, engraved with "u50" on one side.

    Tablets 75 mg

    Oval biconvex tablets covered with a film shell, purple, engraved with "u75" on one side.

    Tablets 100 mg

    Oval biconvex tablets covered with a film shell, grayish-green color, with engraving "u100" on one side.

    Pharmacotherapeutic group:Antiepileptic remedy
    ATX: & nbsp

    N.03.A.X.23   Brivaracetam

    Pharmacodynamics:

    Brivaracetam has a high and selective affinity for the protein synaptic vesicles 2A (SV2A) in the brain - a 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 the exocytosis of neurotransmitters.

    Binding to the glycoprotein of synaptic vesicles 2A (SV2A) seems to be the main mechanism of anticonvulsant effect of brivaracetam.

    Efficacy and safety of clinical use

    The effectiveness of brivaracetam as an adjunctive therapy for partial convulsive seizures (SSP) was established in three randomized, double-blind, placebo-controlled, multi-center studies of the drug at a fixed dose in patients aged 16 years and older.

    The study drug received 1558 patients, of which 1099 patients received brivaracetam in a dose of 5 to 200 mg / day. In all studies, there was an initial 8-week period, followed by a 12-week treatment period without increasing the dose. The study included patients with uncontrolled PSP on the background of taking 1 or 2 concomitant antiepileptic drugs (PEP). During the treatment period, patients were included who had at least 8 CAPs during the initial period.

    The primary endpoints in the 3-phase studies were the percentage reduction in the frequency of PSP versus placebo and the proportion of patients who achieved a decrease in the frequency of the CAP by at least 50% relative to the baseline level. When included in the study, patients most often took such PEPs as carbamazepine (40,6%), lamotrigine (25.2%), valproat (20.5%), oxcarbazepine (16,0%), topiramate (13,5%), phenytoin (10.2%) and levetiracetam (9.8%). When included in all three studies, the median frequency of convulsive seizures in 28 days was 9. The average duration of epilepsy was about 23 years.

    The efficacy of brivaracetam as an additional therapy for PSP in patients aged 16 years and older at doses from 50 mg / day to 200 mg / day was demonstrated.

    In clinical trials, the reduction in the frequency of convulsive seizures compared with the placebo group was more pronounced with brivaracetam administered at a dose of 100 mg / day than 50 mg / day. With the exception of a small dose-related increase in cases of drowsiness and fatigue, the use of brivaracetam at doses of 50 mg / day and 100 mg / day was characterized by comparable safety, including with regard to undesirable phenomena from the CNS and against prolonged therapy.

    According to the combined analysis, the percentage of patients who had a CAP frequency of at least 50% lower than baseline with basal administration of Brivaracetam at doses of 50 mg / day, 100 mg / day, and 200 mg / day was 34.2% , 39.5% and 37.8%, compared with 20.3% in the placebo group (this analysis did not include patients who took levetiracetam).

    In a combined analysis of the data of the three baseline studies, there was no difference in efficacy (defined as a 50% reduction in the CAP frequency relative to baseline) of the dose of brivaracetam in the range of 50 mg / day to 200 mg / day in combination with inducing or non-inducing PEPs.

    During the treatment period, which was 12 weeks, freedom from seizures was achieved in 2.5% (4/161), 5.1% (17/332) and 4.0% (10/249) patients who received brivaracetam in doses of 50 mg / day. 100 mg / day and 200 mg / day, respectively, compared with the placebo group, where it was 0.5% (2/418).

    Reduction in the frequency of convulsive seizures for 28 days was noted in patients who initially suffered IC type of convulsive seizures (secondary generalized tonic-clonic convulsions), who took brivaracetam in doses of 50 mg / day, 100 mg / day and 200 mg / day, by 66.6% (n=62), 61,2% (n= 100) and 82.1% (n= 75), respectively, compared with placebo - by 33.3% (n=115).

    The effectiveness of brivaracetam as monotherapy is not confirmed. Brivaracetam is not recommended for use as a monotherapy.

    Therapy with levetiracetam

    In two randomized, placebo-controlled clinical trials levetiracetam was a concomitant PEP in approximately 20% of patients. Although the number of such patients is limited, it was noted that the benefits of brivaracetam compared with placebo were not observed, which could be a result of competitive binding to the glycoprotein SV2A. Additional problems in the safety and tolerability of this therapy were also not revealed.

    The third study showed the advantage of Brivaracetam at doses of 100 mg / day and 200 mg / day compared with placebo in patients who had previously received levetiracetam. In this subgroup of patients, the lower efficacy of brivaracetam compared to patients not previously treated with levetiracetam may be due to the administration of a larger number of PEPs in the history and a greater initial frequency of convulsive seizures.

    Use in elderly patients (aged 65 years and over)

    In three basic double-blind, placebo-controlled trials, 38 patients aged 65 to 80 years were included. The effectiveness of brivaracetam in elderly patients was comparable to that of younger patients, although the data are limited.

    Use in children

    The effectiveness and tolerability of brivaracetam in children under the age of 16 years are not established (see the section "Pharmacokinetics").

    Open extended studies

    After completion of the randomized trials, 81.7% of patients were included in long open phases of brivaracetam. After 6 months from inclusion in a randomized study, the absence of convulsive seizures was noted in 5.3% (n=1500) patients, in 12 months - in 4.6% (n= 1188) patients and in 24 months - at 3.7% (n= 847) who received brivaracetam. However, considering the fact,that a significant proportion of patients (26%) stopped participating prematurely in extended studies because of lack of efficacy, it can not be ruled out that an unrepresentative sample was included in the data analysis, as the remaining patients responded better to therapy than those who left early.

    Preclinical safety data

    In pharmacological studies of safety, the predominant effect on the central nervous system (mainly, transient CNS depression and decreased spontaneous motor activity) was observed when the drug was administered at doses significantly (more than 50 times) than the pharmacologically active dose of 2 mg / kg brivaracetam. Brivaracetam did not affect learning ability and memory.

    There were no pathological changes in the liver of rats and monkeys with chronic use of brivaracetam in doses much (from 5 to 42 times) exceeding the therapeutic dose of 200 mg / day. Signs of central nervous system damage were registered, which in the course of time weakened (depression, loss of balance, discoordination), in monkeys, when brivaracetam was used at doses 64 times higher than clinical CmOh. In dogs, the use of brivaracetam led to the development of changes in the liver, mainly to porphyria, in doses providing exposure (determined by the area under the concentration-time curve, AUC), close to the average exposure in humans with a dose of 200 mg / day. However, toxicological data on brivaracetam and structurally similar components show that the development of changes in the liver of dogs occurs according to mechanisms not peculiar to humans.

    In studies of genotoxicity, no mutagenic or clastogenic activity was detected. Carcinogenicity studies in rats showed no oncogenic potential, whereas an increased incidence of hepatocellular tumors in male mice was regarded as mediated by a non-genotoxic mechanism of action related to phenobarbital-like induction of hepatic enzymes, which is a known phenomenon specific for rodents.

    Brivaracetam had no effect on the fertility of males and females, there was no teratogenic potential in experiments on rats and rabbits. Embryotoxicity was noted in the application of brivaracetam in pregnant female rabbits in a dose toxic to the female,at which the exposure is 8 times greater than the clinical exposure at the maximum recommended dose. In rats brivaracetam quickly penetrated through the placenta and was excreted with the milk of lactating rats at a concentration close to the concentration in the mother's plasma.

    Studies in rats did not reveal the potential for the development of drug dependence.

    Studies on immature animals

    In immature rats with exposure to brivaracetam, 6-15 times greater than the clinical exposure at the maximum recommended dose, adverse effects on developmental processes (mortality, clinical signs, weight loss and weight loss) were noted.

    There was no negative effect on the function of the central nervous system. as well as neuropathological and histopathological changes in the brain. In immature dogs, when brivaracetam was used in a dose that provided exposure six times higher than the therapeutic level, the changes were similar to those in adult animals.

    No side effects were noted, taking into account standard criteria for evaluating developmental and maturing processes.

    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

    Brivaracetam is rapidly and completely absorbed after ingestion, and its absolute bioavailability is approximately 100%. The median time to reach the maximum concentration (TmOh) when taking fasting tablets is 1 hour (the spread of the values ​​of TmOh from 0.25 to 3 hours).

    Simultaneous reception of brivaracetam with foods high in fat slows down the rate of absorption (median TmOh 3 h) and reduces the maximum concentration of the drug in the plasma by 37%, while the degree of absorption remains unchanged. Distribution

    Brivaracetam binds little to plasma proteins (≤20%). The volume of distribution is 0.5 l / kg, which is close in importance to the total volume of fluid in the body. Due to lipophilicity (Log R) brivaracetam well penetrates through cell membranes.

    Metabolism

    Brivaracetam is primarily metabolized by hydrolysis of the amide component to form the corresponding carboxylic acid (approximately 60% of the dose), again by hydroxylating the propyl side chain (approximately 30% of the dose). Hydrolysis of the amide moiety to form a carboxylic acid (34% of the dose excreted by the kidneys) is mediated by hepatic and extrahepatic amidase. In vitro The hydroxylation of brivaracetam is mediated primarily by the isoenzyme of the cytochrome P450 system CYP2C19. Both metabolites form hydroxylated acid upon further conversion. In vivo in people with an inactive isoenzyme CYP2C19 due to mutation, the formation of hydroxy metabolite is reduced by a factor of 10, while the concentration of brivaracetam is increased by 22% or 42% in subjects with one or both mutated alleles. These three metabolites do not have pharmacological activity.

    Excretion

    Brivaracetam is mainly metabolized and excreted by the kidneys. More than 95% of the dose, including metabolites, is excreted by the kidneys within 72 hours after administration.

    Less than 1% of the dose is excreted by the intestine and less than 10% of the dose is excreted unchanged by the kidneys.The terminal half-life of brivaracetam (T1/2) is approximately 9 hours. The total plasma clearance of brivaracetam in patients is 3.6 l / h.

    Linearity

    Pharmacokinetics is proportional to the dose in the range of 10 to at least 600 mg. Drug Interactions

    Brivaracetam is excreted in several ways, including kidney excretion, not mediated by isoenzymes of the cytochrome P450 system, hydrolysis and mediated by isoenzymes of the cytochrome P450 system oxidation. In studies in vitro shown, that brivaracetam is not a substrate of human glycoprotein (P-gp), of human proteins responsible for multiple drug resistance (MRP1 and MRP2) and, probably, polypeptides-carriers of organic anions 1B1 (OAP1B1) and (OATP1B3).

    Experiments in vitro showed that the biotransformation of brivaracetam is not significantly dependent on isozyme inhibitors CYP (eg, CYP1A, 2C8, 2C9, 2D6 and 3A4).

    In studies in vitro shown, that brivaracetam is not an inhibitor of isoenzymes CYP1A2, 2A6, 2B6, 2C8. 2C9, 2D6, 3A4 or conveyors P-gp, BCRP, BSEP MRP2, MATE-K, MATE-1, OATP1B1, OATP1B3, OAT1 and OSB in concentrations comparable to those used in the clinic. Also in studies in vitro Brivaracetam did not induce isoenzyme CYP1A2.

    Pharmacokinetics in special patient groups

    In the elderly (65 years and over)

    In a study in elderly patients (aged 65-79 years, with a creatinine clearance of 53-98 ml / min / 1.73 m2) who received brivaracetam in a dose of 400 mg / day for two doses, the half-life of the drug was 7.9 hours and 9.3 hours in groups of 65-75 years and older than 75 years, respectively. In an equilibrium state, the clearance of brivaracetam in elderly patients was close (0.76 ml / min / kg) to 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) the concentration of brivaracetam in plasma (determined by AUC) was moderately elevated (by 21%) compared with the same figure in healthy volunteers. At the same time, the concentrations of acidic, hydroxyl and hydroxy-acid metabolites were increased by 3, 4 and 21 times, respectively. The renal clearance of these inactive metabolites decreased 10-fold. According to the results of preclinical studies, the safety of hydroxy-acid metabolites was not a cause for concern.

    Brivaracetam has not been studied in patients on hemodialysis.

    In patients with impaired liver function

    Pharmacokinetic study in patients with cirrhosis of the liver (A, B, C for Child- Pugh) revealed a comparable increase in exposure to brivaracetam, regardless of the severity of the disease (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 brivaracetam solution inside, the concentration of brivaracetam in plasma was proportional to the dose taken in all age groups. Population pharmacokinetic modeling data showed that a dose of 2.0 mg / kg twice daily leads to the same average equilibrium plasma concentration as a dose of 100 mg twice daily for adults.

    Weight Effect

    A decrease in the equilibrium concentration of brivaracetam in plasma was found to be 40% in patients with body weight ranging from 46 to 115 kg. However, this difference in the pharmacokinetics of brivaracetam is regarded as clinically insignificant.

    Effect of sex

    Clinically significant differences in the pharmacokinetics of brivaracetam in patients of different sexes have not been revealed.

    Influence of the race

    The race (europoid, Mongoloid) did not significantly affect the parameters of the pharmacokinetics of brivaracetam, according to the results of population pharmacokinetic modeling in patients with epilepsy.The number of patients of another ethnic origin was limited.

    Pharmacokinetic / pharmacodynamic relationship

    The concentration of Brivaracetam in plasma, which is 50% of the maximum effective concentration (EC50), corresponds to 0.57 mg / l. This concentration in the plasma slightly exceeds the median exposure value of brivaracetam after taking a dose of 50 mg / day. A further decrease in the frequency of convulsive seizures was noted with an increase in the dose to 100 mg / day, the efficacy reached a plateau when taking the drug at a dose of 200 mg / day.

    Indications:

    Briviak is indicated as an adjunctive therapy in the treatment of partial convulsive seizures with secondary generalization or without it in adults and adolescents with age 16 suffering from epilepsy.

    Contraindications:

    - Hypersensitivity to the active substance or other pyrrolidone derivatives, as well as any of the auxiliary components listed in the "Composition" section.

    - Children under 16 years of age (due to the lack of clinical data).

    - Rare hereditary intolerance to galactose, deficiency of lactase or glucose-galactose malabsorption.

    - Terminal renal failure requiring hemodialysis (due to the lack of clinical data).

    Carefully:

    Patients with:

    - suicidal thoughts and suicide attempts

    - violations of the liver (see sections "Method of administration and dose" and "Special instructions ").

    Pregnancy and lactation:

    Pregnancy

    The risk caused by epilepsy and antiepileptic drugs

    Among children born to women who received antiepileptic drugs, the number of congenital malformations is 2-3 times higher than the value of about 3%, typical for the population as a whole. Simultaneous therapy with several antiepileptic drugs is associated with a higher risk of congenital malformations, but the contribution of each drug and / or the disease itself was not assessed separately.

    Termination of antiepileptic therapy can lead to an exacerbation of the disease, which, perhaps, will be dangerous for the mother and fetus.

    The risk of brivaracetam

    Studies of brivaracetam on animals have not revealed a teratogenic potential.

    Data of brivaracetam use in pregnant women are limited.

    In clinical studies using brivaracetam as adjunctive therapy in combination with carbamazepine, a dose-dependent increase in the concentration of the active metabolite of carbamazepine-carbamazepine epoxide was noted (see section "Interaction with other drugs"). Data for determining the clinical significance of this effect in pregnant women is not enough. There are no data on the penetration of brivaracetam through the placental barrier in humans. In rats brivaracetam easily penetrates the placenta. The potential risk to humans is unknown.

    Brivaracetam should not be used during pregnancy, except in cases of clinical necessity, when the benefit to the mother clearly exceeds the potential risk to the fetus.

    Stopping brivaracetam may cause an exacerbation of the disease, which can be dangerous for the mother and fetus.

    Breast-feeding

    It is not known whether brivaracetam with human breast milk. In lactating rats brivaracetam is excreted with milk. The decision to stop breastfeeding or taking brivaracetam is based on an assessment of the need for therapy for the mother.With the simultaneous administration of brivaracetam and carbamazepine, an increase in the amount of carbamazepine epoxide is possible. excreted into breast milk. Data for assessing clinical significance is not enough.

    Fertility

    There is no data on the effect of Brivaracetam on human fertility. In rats reception of brivaracetam did not affect fertility.

    Women with preserved childbearing potential

    Before prescribing brivaracetam, the physician should discuss family planning and contraceptive measures with women in whom the childbearing function is preserved. When planning a woman's pregnancy, the question of continuing to take brivaracetam should be reviewed.

    Dosing and Administration:

    Inside, not liquid, squeezed water, regardless of food intake (see section "Pharmacological properties").

    The recommended initial dose is 50 mg / day or 100 mg / day, according to the decision of the attending physician, based on the required anticonvulsant effect and the potential side effect. The daily dose is divided equally into two doses, in the morning and in the evening. Depending on the patient's individual response and tolerability, the dose can be varied from 50 mg / day to 200 mg / day, in which brivaracetam is effective as a concomitant therapy for PSP. Initial titration of the dose to an effective dose does not require recording the tolerability of brivaracetam therapy.

    In case of missing one or more doses, it is recommended to take the missed dose of the drug as soon as possible; the next dose is taken at regular time in the morning or evening. Replenishment of the missed dose will avoid reducing the concentration of brivaracetam in the plasma below the effective level and prevent recurrence of convulsive seizures.

    Abolition of the drug

    If necessary, discontinue treatment with Brivaracetam, it is recommended to cancel the drug gradually, reducing the dose by 50 mg / day per week. After one week of taking a dose of 50 mg / day, it is recommended that the last week be taken brivaracetam in a dose of 20 mg / day.

    Features of application for particular groups patients

    Elderly (65 years and over)

    Dose adjustments in elderly patients are not required (see section "Pharmacokinetics"), experience in patients aged 65 years and older is limited.

    Impaired renal function

    Dose adjustments in patients with impaired renal function are not required (see section "Pharmacokinetics"). Brivaracetam It is not recommended in patients with terminal renal failure who need hemodialysis, due to the lack of clinical data.

    Impaired liver function

    In patients with chronic liver diseases, exposure to brivaracetam is increased. You should start with a dose of 50 mg / day. The recommended maximum daily dose for all stages of liver failure is 150 mg divided into two doses (see section "Pharmacokinetics").

    Children

    The safety and efficacy of brivaracetam in newborns and children under the age of 16 years have not been established.

    The data obtained so far are indicated in the sections "Side effect" and "Pharmacological properties".

    Side effects:

    Security Profile Summary

    The safety of Briviak was evaluated in 2388 patients, of which 1740 received brivaracetam for ≥ 6 months, 1363 patients - ≥ 12 months, 923 - ≥ 24 months and 569 - ≥ 60 months (5 years).

    Most often (> 10%), when treated with brivaracetam, drowsiness (14.3%) and dizziness (11.0%) were noted. These undesirable drug reactions (NLR) usually had mild or moderate severity. The incidence of drowsiness and fatigue (8.2%) increased with an increase in the dose of the drug.The types of adverse reactions observed during the first 7 days of therapy were similar to those recorded during the entire treatment period.

    The frequency of early termination of therapy due to development of NLR was 3.5%, 3.4% and 4.0% in patients randomized to receive brivaracetam at doses of 50 mg / day, 100 mg / day and 200 mg / day, respectively; the analogous parameter in the placebo group was 1.7%. The most frequent NLR, leading to an early withdrawal of brivaracetam, were dizziness (0.8%) and convulsions (0.8%).

    NLR are presented in accordance with the defeat of organs and systems of organs (MedDRA) and classification by frequency: very often (≥ 1/10); often (≥ 1/100, but <1/10) and infrequently (≥ 1/1000, but <1/100).

    Infectious and parasitic diseases

    Often: influenza

    Violations of the blood and lymphatic system

    Infrequently: neutropenia

    Disorders from the metabolism and nutrition

    Often: Decreased appetite

    Disorders of the psyche

    Often: Depression, anxiety, insomnia, irritability

    Infrequently: Suicidal thoughts, psychotic disorder, aggressiveness, agitation

    Disturbances from the nervous system

    Often: dizziness, drowsiness

    Often: convulsions, vertigo

    Disturbances from the respiratory system, chest and mediastinal organs

    Often: upper respiratory tract infection, cough

    Disorders from the gastrointestinal tract

    Often: nausea, vomiting, constipation

    General disorders and disorders at the site of administration

    Often: fatigue

    Description of selected NLRs

    Neutropenia was noted in 0.5% (6 of 1099) of patients who received brivaracetam, and 0% (0 of 459) of patients receiving placebo. In 4 of these patients, the number of neutrophils was initially reduced, and a further decrease in the index was noted with treatment with brivaracetam. None of the 6 cases of neutropenia was serious, did not require special treatment, did not lead to discontinuation of brivaracetam and was not accompanied by infectious complications.

    Suicidal intentions were noted in 0.3% (3 of 1099) of patients who received brivaracetam, and 0.7% (3 of 459) of the patients receiving the placebo. In the framework of short-term clinical studies of the use of brivaracetam in patients with epilepsy, no suicide and suicidal attempts have been reported, but both of these phenomena have been recorded in the open-label phase of open-label study.

    Open extended studies

    The safety profile of brivaracetam in short-term placebo-controlled trials was comparable to its safety profile in patients who continued to use the drug in prolonged open phases for up to 8 years. Use in children

    Data on the safety of brivaracetam in open studies in children aged 1 month to <16 years are limited. In total, 152 children (from 1 month to <16 years) received brivaracetam in the study of pharmacokinetics and follow-up. According to the limited information available, the most common adverse events regarded by the investigating physician as related to the drug were drowsiness (10%), decreased appetite (8%), fatigue (5%) and weight loss (5%). The safety profile of children was comparable to the safety profile of brivaracetam in adults. Data on the effect on the development of the nervous system are absent. At present, there is no information on the results of the clinical use of the drug in newborns.

    Application in the elderly

    Of the 130 elderly patients enrolled in clinical studies of 2-3-phase brivaracetam (44 with epilepsy), 100 patients were aged 65-74 years and 30 patients aged 75 to 84 years.The safety profile of brivaracetam was similar in elderly patients and in younger adult patients.

    Overdose:

    The clinical experience of an overdose of brivaracetam in humans is limited. In healthy volunteers who took single-dose brivaracetam in a dose of 1400 mg, there was drowsiness and dizziness.

    There is no specific antidote for brivaracetam. In case of an overdose, general supportive therapy is provided. Since less than 10% of brivaracetam is excreted in the urine, it is unlikely that hemodialysis will significantly increase the clearance of brivaracetam (see section "Pharmacological properties").

    Interaction:

    Studies of inter-drug interactions were conducted only in adults. Pharmacodynamic interactions

    Combined use with levetiracetam

    In a limited number of clinical studies, the benefits of brivaracetam compared with placebo in patients taking concomitantly levetiracetam. There was no additional effect on safety or tolerability (see the section "Pharmacodynamics").

    Interaction with ethanol

    In a study of the pharmacokinetic and pharmacodynamic interaction between brivaracetam (with a single dose of 200 mg) and ethanol (with its long infusion at a concentration of 0.6 g / l), no healthy volunteers of pharmacokinetic interaction were observed. However, the effect of alcohol on the psychomotor function, attention and memory was doubled with simultaneous use with brivaracetam. It is not recommended to drink alcohol on the background of brivaracetam therapy.

    Pharmacokinetic interactions

    The effect of other drugs on the pharmacokinetics of brivaracetam

    Brivaracetam has a low potential for participation in inter-drug interactions in vitro. The main way of biotransformation of brivaracetam is in CYP-independent hydrolysis. The second pathway of biotransformation involves hydroxylation mediated by an isoenzyme CYP2C19 (see section "Pharmacokinetics"). It is possible to increase the concentration of brivaracetam when it is combined with potent inhibitors of isoenzyme CYP2C19 (fluconazole, fluvoxamine), but the risk of clinically significant interaction mediated by isoenzyme CYP2C19, is considered low.

    Rifampicin

    Simultaneous use in healthy volunteers with a powerful inducer of rifampicin (600 mg / day for 5 days) was accompanied by a 45% decrease in the exposure value of brivaracetam. The dose of brivaracetam should be adjusted in patients starting or completing rifampicin therapy.

    PEP, which are powerful inducers of enzymes

    The concentration of brivaracetam in blood plasma is reduced when it is used together with PEP, which are powerful inducers of enzymes (carbamazepine, phenobarbital, phenytoin), however, no dose adjustment is required in this situation (see Table 1).

    Other inducers of enzymes

    Other powerful enzyme inducers (such as St. John's wort) can also reduce the systemic exposure of brivaracetam. Therefore, care should be taken at the beginning and at the conclusion of the reception of St. John's wort perforated against the background of treatment with brivaracetam.

    Influence of Brivaracetam on other drugs

    Brivaracetam at doses of 50 to 150 mg / day did not affect AUC midazolam (metabolized by isoenzyme CYP3A4). Risk of development of clinically significant isozyme mediated interactions CYP3A4, is considered low. Research in vitro showed that brivaracetam inhibits isoenzymes CYP450 to a small extent, or does not inhibit them at all, except for CYP2C19. Brivaracetam can increase the concentration in the blood plasma of drugs metabolized with the participation of isoenzyme CYP2C19 (e.g., lansoprazole, omeprazole, diazepam). In experiments in vitro Brivaracetam did not induce isoenzyme CYP1A1/2, but induced isoenzymes CYP3A4 and CYP2B6. No induction of isoenzyme observed CYP3A4 in vivo (cm. midazolam higher). Effect on isoenzyme CYP2B6 not studied in vivo, brivaracetam can reduce the concentration in the blood plasma of drugs metabolized with the participation of isoenzyme CYP2B6 (e.g. efavirenz).

    In studies in vitro inter-drug interaction in order to assess the potential inhibitory effect of the drug on transporters, it was concluded that there were no clinically significant effects, with the exception of the effect on carrier of organic anions 3 (OAT3). Concentration of brivaracetam in vitro, providing 50% of the maximum inhibitory OATZ effect, was 42 times higher than CmOh when the maximum therapeutic dose is taken. Brivaracetam in a dose of 200 mg / day can increase the concentration in the blood plasma of drugs carried OATS.

    Antiepileptic agents

    Potential interactions between Brivaracetam (in doses of 50 to 200 mg / day) and other PEPs were evaluated in a pooled analysis of plasma concentrations of the drug obtained in all Phase 2 and Phase 3 trials (including the population pharmacokinetic analysis of placebo-controlled trials 2 and 3 phase), and in special studies of drug interactions for the following PEP: carbamazepine, lamotrigine, phenytoin and topiramate. Influence data interactions on plasma drug concentrations are shown in Table 1.

    Table 1. Interactions between brivaracetam and other antiepileptic drugs

    At the same time, the received PEP

    Effect of PEP on the concentration of brivaracetam in blood plasma

    Effect of Brivaracetam on the concentration of PEP in blood plasma

    Carbamazepine

    Decrease AUC 29% Decrease in Cmax 13% No dose correction required

    Does not affect

    Increase in the concentration of carbamazepine epoxide (see below)

    Correction of the dose is not required.

    Clobazam

    No data available

    Does not affect

    Clonazepam

    No data available

    Does not affect

    Lacosamide

    No data available

    Does not affect

    Lamotrigine

    Does not affect

    Does not affect

    Levetiracetam

    Does not affect

    Does not affect

    Oxcarbazepine

    Does not affect

    Does not affect

    (monohydroxylated

    derivative)

    Phenobarbital

    Decrease AUC 19% No dose correction required

    Does not affect

    Phenytoin

    Decrease AUC by 21%

    Does not affect


    Dose correction is not required

    a Increase AUC by 20%

    a Increase CmOh by 20%

    Pregabalin

    No data available

    Does not affect

    Topiramate

    Does not affect

    Does not affect

    Valproic acid

    Does not affect

    Does not affect

    Zonisamide

    No data available

    Does not affect

    a no a study that included the use of brivaracetam in doses above therapeutic (up to 400 mg / day).

    Carbamazepine

    Brivaracetam is a moderate reversible inhibitor of epoxide hydrolase, which increases the concentration of carbamazepine epoxide (the active metabolite of carbamazepine) in the blood. In controlled studies, carbamazepine epoxide concentrations in the blood plasma increased by an average of 37%, 62%, and 98% (with low variability), while concomitantly using Brivaracetam at doses of 50 mg / day, 100 mg / day, or 200 mg / day, respectively.The security profile has not changed. There was no additional effect of brivaracetam and valproate on AUC epoxy carbamazepine.

    Oral contraceptives

    Combined use of brivaracetam (100 mg / day) with an oral contraceptive containing ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg) had no effect on the pharmacokinetics parameters of any of the components of this combination. When concomitantly taking brivaracetam 400 mg / day (in a dose exceeding the recommended maximum daily dose by a factor of 2) with an oral contraceptive containing ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg) there was a decrease in the values AUC estrogen and progestin by 27% and 23%, respectively, which did not affect the degree of suppression of ovulation. There are no recorded changes in the concentration-time profiles for endogenous markers of estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone and globulin binding sex hormones.

    Special instructions:

    Abolition of the drug

    If necessary, discontinue treatment with Brivaracetam, it is recommended to cancel the drug gradually, reducing the dose by 50 mg / day per week.After one week of taking a dose of 50 mg / day, it is recommended that the last week be taken brivaracetam in a dose of 20 mg / day.

    Suicidal intentions and suicide attempts

    Suicidal intentions and suicide attempts were noted in patients who received G1EG1, including brivaracetam, for different indications. A meta-analysis of the results of randomized placebo-controlled studies of PEP also showed a slight increase in the risk of suicidal intentions and attempts. The mechanism of occurrence of suicide risk is unknown, and the possibility of increasing the risk with brivaracetam is not excluded.

    It is necessary to monitor the signs of suicidal intentions and attempts in patients, to start the appropriate treatment in a timely manner. Patients (and carers) should be informed of the need to seek medical help immediately if suicidal intentions or attempts occur. Impaired liver function

    Clinical data on the use of brivaracetam in patients with hepatic impairment are limited. It is recommended to correct the dose of the drug in patients with impaired liver function (see section "Method of administration and dose").

    Effect on the ability to drive transp. cf.and fur:

    Brivaracetam slightly or moderately affects the ability to drive vehicles and other mechanisms.

    Due to differences in individual sensitivity to the drug, drowsiness, dizziness and other CNS effects may develop in a number of patients. Patients are advised not to drive the car and not work with other potentially dangerous mechanisms until the impact of Brivaracetam on their ability to perform such activities becomes clear to them.

    Form release / dosage:

    Film-coated tablets, 10 mg, 25 mg, 50 mg, 75 mg and 100 mg.

    Packaging:

    Packing with blisters for 14 tablets

    For 14 tablets in a blister of PVC / PTFE and aluminum foil. For 1 blister (for tablets 10 mg) or for 4 blisters (for tablets 25 mg, 50 mg, 75 mg and 100 mg) together with instructions for use in a cardboard pack.

    The cardboard tutu has a first-tamper control system and a protective hologram.

    Packing with individual blisters, intended for hospitals

    1 tablet per individual blister made of PVC / PTFE and aluminum foil. 100 individual blisters together with 5 instructions for use in a cardboard box.

    The cardboard tutu has a first-tamper control system and a protective hologram.

    HOLIDAY CONDITIONS

    Packing with blisters for 14 tablets - "Let go of the prescription."

    Packing with individual blisters - "For hospitals".
    Storage conditions:

    Store at a temperature not exceeding 30 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiry date indicated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004084
    Date of registration:18.01.2017
    Expiration Date:18.01.2022
    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: & nbsp30.01.2017
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