Бринтелликс

General characteristics. Structure:

Acting вещетво: 5 mg or 10 mg of a vortioksetin in the form of a vortioksetin of a hydrochloride.

Excipients: mannitol (Е 421), cellulose microcrystallic, hydroxypropyl cellulose, starch sodium (type A), magnesium stearate, gipromelloz, macrogoal 400, titanium dioxide (E 171); tablets of 5 mg ferrous oxide red (E172); tablets of 10 mg ferrous oxide yellow (Е 172).

Pharmacological properties:

Pharmacodynamics. Action mechanism. The mechanism of action of a vortioksetin as believe, is connected with its multimodal activity which is a combination of two pharmacological mechanisms: direct modulation of activity of receptors and inhibition of the conveyor of serotonin (5-HT). Preclinical data show what вортиоксетин is an antagonist 5-HT 3, 5-HT of 7 and 5-HT 1D receptors, a partial agonist of 5-HT 1B receptors, an agonist of 5-HT 1A receptors and inhibitor 5-HT of the conveyor, causes modulation of neurotransmission in several systems, including serotonin, noradrenaline, dopamine, a histamine, acetylcholine, GAMK and a glutamate. Such multimodal activity as believe, provides antidepressants and anxiolytic effects, and also improvement of cognitive function, training and memory in the conditions of preclinical trials of a vortioksetin. Besides, preclinical trials specify what вортиоксетин does not cause sexual dysfunction. The exact contribution of each component of this mechanism to an observed pharmakodinamichesky profile remains not clear therefore it is necessary to apply attention at extrapolation of preclinical data directly on the person.

It is established that capture of the conveyor of serotonin various daily doses of a vortioksetin about 50% - a dose of 5 mg made, 65% - in a dose of 10 mg and more than 80% - a dose of 20 mg. Vortioksetin clinically showed antidepressive action at capture of the conveyor 5-HT for 50%.

Clinical performance and safety. Efficiency of a vortioksetin increases with increase in a dose. Besides вортиоксетин within doses of 5-20 mg showed efficiency with the broad range depressive (on MADRS scale) and alarming (on HAM-A scale) depression symptoms.

Prevention of a recurrence. Duration of antidepressive effect was shown in a research of prevention of a recurrence in which the risk of a recurrence is twice higher was defined in group of placebo, than in group to a vortioksetin.

Patients of advanced age. In the range of doses of a vortioksetin from 5 to 20 mg a day efficiency and portability at elderly people answered results of researches at adult population.

Patients with a heavy depression or high level of symptoms of alarm. Antidepressant efficiency was also shown at patients with a heavy depression (≥ 30 points of MADRS) and in depressive patients with the high level of alarming symptoms (≥ 20 points of HAM-A) in short-term researches, including researches at patients of advanced age, and long-term researches of prevention of a recurrence.

Patients with the inadequate response to treatment of SIOZS / SIZZN. In a comparative research of flexible doses at patients with a depression after the inadequate response to treatment of the existing episode of SIOZS / SIZZN вортиоксетин in a daily dose of 10-20 mg was statistically much more effective what агомелатин in a dose of 25-50 mg (on MADRS scale), clinical value was proved on scales of CGI-I and SDS.

Cognitive dysfunction at a depression. During the researches of influence of medicine on cognitive processes it turned out that the effect to a vortioksetin is mainly caused by direct impact on cognitive function, than an indirect impact through improvement of symptoms of a depression.

Quality of life and general functioning. Vortioksetin surpassed placebo in indicators of assessment of quality of life, clinically considerably improved the general state of health (on EQ-5D scale) and indicators of the general functioning (on SDS scale - work, social and family lives) in comparison with placebo or active means of comparison (agomelatiny). Moreover, the best effects in comparison with placebo concerning quality of life remained during the long-term research of prevention of a recurrence.

Portability and safety. Safety and portability of a vortioksetin were estimated in short and long-term researches for doses of 5-20 mg a day.

Wortiokxieting NIE increased frequencies sleeplessness or drowsiness in comparison with placebo.

In systematic to assessment of potential symptoms of cancellation clinically significant difference between vortioksetiny and placebo on the frequency and character of symptoms of cancellation after short-term (6-12 weeks), after long-term (24-64 weeks) the treatment period was not revealed.

During clinical trials to a vortioksetin the frequency of messages about undesirable sexual reactions was low and similar placebo, indicators of frequency of the sexual dysfunction connected with therapy, and the general estimates on a scale of ASEX had no clinically significant distinctions with placebo concerning symptoms of sexual dysfunction at use of the recommended dose of a vortioksetin, but high doses were connected with the numerical growth of cases of dysfunction.

During clinical trials like placebo вортиоксетин did not influence the body weight, heart rate and arterial pressure.

Clinically significant changes in estimates of function of a liver and kidneys during clinical trials were not.

Vortioksetin did not exert any clinically significant impact on the ECG parameters, including QT-, QTc-, PR - and QRS intervals, at patients with big depressive frustration. In the careful research QTc among healthy volunteers at use of doses to 40 mg in days of potential to increase in QTc the interval was not observed.

Children's age. Clinical trials among patients of children's age were not conducted, therefore, safety and efficiency of drug. Бринтелликс for patients aged up to 18 years were not established.

Pharmacokinetics. Absorption. Vortioksetin slowly, but is well soaked up after intake and the peak of concentration in a blood plasma is reached within 7-11 hours. After multiple dose of 5, 10 or 20 mg a day average C Max value of 9-33 ng/ml was observed. Bioavailability makes 75%. Influence of meal on pharmacokinetics was not observed.

Distribution. The average volume of distribution (the V SS) makes 2600 l that specifies on volume extravasated distribution. Vortioksetin strongly contacts proteins of plasma (98-99%) and binding as it is represented, does not depend on concentration of a vortioksetin in plasma.

Metabolism. Vortioksetin is widely metabolized in a liver, mainly by oxidation and the subsequent conjugation by glucuronic acid.

In vitro isoenzymes of P450 CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 cytochrome participate in metabolism of a vortioksetin. The inhibiting or inducing influence of a vortioksetin of in vitro on isoenzymes of CYP CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5 was not observed. Vortioksetin is weak P-gp substrate and inhibitor.

Main metabolite of a vortioksetin pharmacological inactive.

Removal the Elimination half-life - 66 hours. About 2/3 inactive metabolites of a vortioksetin are removed with urine and about 1/3 - with a stake. Only the insignificant quantity of a vortioksetin is removed with a stake. Resistant concentration in a blood plasma is reached in 2 weeks.

Linearity/nonlinearity. The pharmacokinetics linear also does not depend on time in the range of the studied doses (2,5-60 mg a day). According to half-life the index of accumulation makes from 5 to 6 on the basis of AUC 0-24 after several receptions of doses from 5 to 20 mg a day.

Patients of advanced age. At elderly healthy volunteers (aged ≥ 65 years, n = 20) influence of a vortioksetin increased by 27% (C Max and AUC) in comparison with young healthy volunteers of control group (aged ≤ 45 years) after several receptions of 10 mg a day. Dose adjustment is not required.

Renal failure. After a single dose of 10 mg of a vortioksetin the renal failure (on Kokrofta-Gault's formula, easy, average or heavy, n = 8 in group) caused insignificant increase in exposure (to 30%) in comparison with that at control group of healthy volunteers. At patients with an end-stage of a renal failure only the small fraction of a vortioksetin was lost during dialysis process (AUC and C Max for 13% and 27% is lower; n = 8) after a single dose of 10 mg of a vortioksetin. Dose adjustment is not required.

Liver failure. After a single dose of 10 mg of a vortioksetin of influence of a slight or moderate liver failure (Child-Pugh, criterion And yes In; n=8 in each group) on pharmacokinetics of a vortioksetin was not observed (changes of AUC made less than 10%). Dose adjustment is not required. Vortioksetin did not investigate at patients with a heavy liver failure, and it is necessary to show care at appointment to these patients.

Weak metabolizator of CYP2D6. In weak concentration to a vortioksetin in a blood plasma was approximately twice higher than CYP2D6 metabolizator, than in extensive metabolizator. In the presence of powerful CYP3A4/2C9 of inhibitors influence can be potentially higher. Dose adjustment can be required, as well as for all patients, depending on individual reaction.

Indications to use:

Treatment of big depressive frustration at adults.

Route of administration and doses:

Бринтелликс accept inside with food or without. The initial and supporting doses make 10 mg once a day.

Depending on individual sensitivity of the patient it is possible to increase a dose as much as possible to 20 mg a day or to lower minimum to 5 mg a day.

After elimination of symptoms of a depression it is recommended to continue treatment of 6 more months for strengthening of antidepressive effect.

Treatment termination. Treatment by Brintelliks can be stopped sharply, there is no need of a gradual dose decline.

Special groups of patients. Patients of advanced age. Dose adjustment for patients of advanced age only on the basis of age is not required.

P450 cytochrome inhibitors. Depending on individual reaction of the patient the vortioksetin should consider use of low doses if powerful CYP2D6 inhibitors are added to therapy (for example бупропион, quinidine, fluoxetine, пароксетин).

P450 cytochrome inductors. Depending on individual reaction of the patient the vortioksetin should consider dose adjustment if the P450 cytochrome inductor is added to therapy (for example rifampicin, carbamazepine, Phenytoinum).

Children. Safety and Brintelliksu's efficiency for treatment of a depression at patients aged up to 18 years were not established, therefore, use is not recommended.

Features of use:

Use in pediatric population of patients. Бринтелликс it is not recommended for treatment of a depression at patients aged up to 18 years as safety and efficiency for this age group it is not established. During clinical trials at children to whom applied other antidepressants the suicide behavior (suicide attempts and suicide thoughts) and hostility (preferential aggression, oppositional behavior, anger) observed more often than at patients to whom they applied placebo.

Suicide / suicide thoughts. The depression is connected with the increased risk of suicide thoughts, self-damage and a suicide (the events connected with suicide). This risk remains before achievement of considerable remission. As improvement can not happen within the first several weeks of treatment or more, it is necessary to control carefully a condition of patients so far there is an improvement. From the general clinical experience it is known that the risk of a suicide can increase at early stages of recovery.

Patients with the anamnesis of the events connected with suicide or with the available considerable signs of suicide thoughts prior to treatment, as we know, are subject to bigger risk of suicide thoughts or attempts of suicide and demand careful observation during treatment. The metaanalysis of placebo - controlled clinical tests of antidepressants at adult patients with mental disorders showed the increased risk of suicide behavior in comparison with placebo at patients aged up to 25 years.

Strict supervision of patients and, in particular, behind persons with high risk has to accompany treatment, especially at the beginning of therapy and after change of a dose. Patients (and their trustees) should be warned about need of monitoring of any clinical deterioration, suicide behavior or thoughts and unusual changes in behavior, and also about need to see a doctor immediately if there are these symptoms.

Spasms. Spasms are potential risk at use of antidepressants. Therefore treatment vortioksetiny should be begun with care at patients who have spasms in the anamnesis, or at patients with unstable epilepsy. Treatment of any patient should be stopped if attacks develop or their frequency increases.

Serotoninovy syndrome or antipsychotic malignant syndrome. The Serotoninovy syndrome (CC) or the antipsychotic malignant syndrome (AMS), potentially life-threatening states, can develop in time of treatment of Brintelliks. The risk of development of CC and NZS increases at simultaneous use of serotonergic means (including triptanes), the means influencing serotonin metabolism (including MAO inhibitors), anti-psychotics and other antagonists of a dopamine. It is necessary to control attentively manifestations of symptoms of CC or NZS.

Symptoms of CC include changes of mental condition (such as excitement, hallucinations and coma), vegetative instability (for example tachycardia, labile blood pressure and a hyperthermia), neuromuscular aberrations (such as hyperreflexia, lack of coordination) and/or gastrointestinal symptoms (for example nausea, vomiting and diarrhea). At emergence of such signs it is necessary to stop immediately use of drug of Brintelliks and to begin a symptomatic treatment.

Mania / hypomania. Бринтелликс patients should appoint with care with the anamnesis of a mania / hypomania and to stop use if gained development a maniacal phase.

Bleeding As well as at use of any other antidepressant serotonergic action (SIOZS, SIZZN), abnormal hemorrhages, such as bruises, a purpura and other bleedings, such as gastrointestinal or gynecologic bleeding are possible. Care on the patients accepting the anticoagulants and/or medicines influencing function of thrombocytes (for example atypical antipsychotic and fenotiazina, the majority of TTsA, non-steroidal anti-inflammatory drugs, acetylsalicylic acid), and also patients with the known tendency to bleeding or blood coagulation disturbances is recommended.

Hyponatremia. About a hyponatremia probably because of inadequate secretion of ADG, at use of antidepressants of the SIOZS, SIZZN groups it was reported seldom. It is necessary to be careful for patients with risk of development of a hyponatremia as patients of advanced age, with cirrhosis, or at simultaneous use of the drugs causing a hyponatremia. With a symptomatic hyponatremia it is reasonable to patients to stop Brintelliksu's use and to begin the corresponding medical intervention.

Renal failure. Data on use to patients with heavy insufficiency are limited, therefore, it is necessary to show care.

Liver failure. Vortioksetin did not investigate at patients with a heavy liver failure, it is necessary to show care at treatment of such patients.

Use during pregnancy or feeding by a breast. Pregnancy. Experience of use of a vortioksetin by pregnant women is limited.

In researches on animals teratogenic effect it is not established, but decrease in body weight and a delay of ossification of a fruit was observed.

After use to women at late stages of pregnancy of serotonergic medicines at newborns the following symptoms can be shown: respiratory distress, cyanosis, asthma, spasms, temperature instability, difficulties of feeding, vomiting, hypoglycemia, hypertension, hypotonia, hyperreflexia, tremor, nervousness, irritability, slackness, constant crying, drowsiness and difficulties with a dream. These symptoms can be connected with effects of cancellation or excessive serotonergic activity. In most cases such complications begin immediately or in the nearest future (<24 hours) after the delivery.

Epidemiological data showed that use of SIOZS during pregnancy, especially on late terms, can lead to increase in risk of persistent pulmonary hypertensia at newborn (PLGN). Though communication of PLGN with treatment vortioksetiny was not studied, this potential risk cannot be excluded, considering the action mechanism (growth of concentration of serotonin).

Бринтелликс it is not necessary to apply during pregnancy if the clinical condition of the woman does not demand treatment vortioksetiny.

Breastfeeding. The available preclinical data showed removal to a vortioksetin and metabolites in breast milk. It is expected that вортиоксетин it is allocated in breast milk. The risk for the baby cannot be excluded. The decision on feeding termination/continuation by a breast or termination / deduction from treatment by Brintelliks should be accepted taking into account advantage of breastfeeding for the child and advantage of therapy for the woman.

Fertility. The fertility research at males and females of animals was not shown by impacts of a vortioksetin on fertility, quality of sperm and productivity of pairing.

Ability to influence speed of response at control of motor transport or other mechanisms. Essential disturbance of ability to manage motor transport, cognitive functions or other psychomotor skills in comparison with placebo at healthy volunteers were not observed. However patients have to show care during the driving or operation of dangerous mechanisms.

Side effects:

Nausea was the most frequent side reaction. Side reactions were usually easy or moderate and were observed within the first two weeks of treatment. Reactions, as a rule, were passing and usually did not lead to the therapy termination. From the alimentary system (for example nausea) were more often observed at women, than at men. The side reactions given below are defined as: very often (≥ 1/10), it is frequent (≥ 1/100 to <1/10), infrequent (≥ 1/1000 to <1/100), rare (≥ 1/10 000 to <1/1000), very rare (<1/10 000) and unknown (frequency cannot be established according to the available data).

System, body, class	Frequency	Side reaction
From food and a metabolism:	Often:	Loss of appetite
From mentality:	Often:	Pathological dreams
	Infrequently:	Bruxism
From a nervous system:	Often:	Dizziness
From cardiovascular system:	Infrequently:	Flush
From the alimentary system:	Very often:	Nausea
	Often:	Diarrhea, lock, vomiting
From skin and hypodermic cellulose:	Often:	The itch is generalized
	Infrequently:	Perspiration at night

Interaction with other medicines:

Vortioksetin is metabolized in a liver mainly by oxidation and the subsequent conjugation by glucuronic acid. In vitro to a vortioksetin participate in metabolism isoenzymes of P450 CYP2D6 cytochrome, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6.

Influence of other medicines on action of a vortioksetin. MAO irreversible non-selective inhibitors

Due to the risk of a serotoninovy syndrome вортиоксетин it is contraindicated in any combination with the MAO irreversible non-selective inhibitors. Treatment vortioksetiny should not be begun earlier at least in 14 days after the treatment termination with the MAO irreversible non-selective inhibitors. Reception of a vortioksetin should be stopped at least in 14 days prior to treatment by the MAO irreversible non-selective inhibitors.

MAO-A reverse selection inhibitor (моклобемид). A combination of a vortioksetin with the MAO-A reverse selection inhibitor, such as моклобемид, it is contraindicated. Careful monitoring of a serotoninovy syndrome at simultaneous use it is necessary.

MAO reverse non-selective inhibitor (линезолид). The combination of a vortioksetin with weak reversible and the MAO non-selective inhibitor, such as an antibiotic линезолид, is contraindicated. Careful monitoring of a serotoninovy syndrome at simultaneous use it is necessary.

MAO-B non-current selection inhibitors (селегилин, разагилин). Despite lower (than with MAO-A inhibitors) the expected risk of a serotoninovy syndrome, a combination of a vortioksetin to the MAO-B irreversible inhibitors, such as селегилин or разагилин, it is necessary to carry out with care. Careful monitoring of a serotoninovy syndrome at simultaneous use it is necessary.

Serotonergic medicines. Co-administration with serotonergic medicines (for example, with tramadoly, суматриптан and others triptanes) can bring to a serotoninovy syndrome.

St. John's Wort. Simultaneous use of antidepressants serotonergic action and the vegetable means containing the St. John's Wort which is made a hole can lead to increase in frequency of side reactions, including serotonin a syndrome.

Medicines which reduce a convulsive threshold. Antidepressants serotonergic actions can lower a threshold of convulsive readiness. Care at simultaneous use of other medicines capable to lower a threshold of convulsive readiness (as antidepressants (TTsA, SIOZS, SIZZN), neuroleptics is recommended (fenotiazina, thioxanthenes, phenyl propyl ketones), мефлохин, бупропион and трамадол).

ECT (electroconvulsive therapy). The vortioksetin does not have clinical experience of simultaneous use with EST therefore care is reasonable.

P450 cytochrome inhibitors. At introduction together with 150 mg of a bupropion (strong CYP2D6 inhibitor) twice a day within 14 days at healthy volunteers influence to a vortioksetin increased by 2,3 times for AUC. Joint introduction led to increase in frequency of side effects at addition of a bupropion to a vortioksetin more often, than at addition of a vortioksetin to a bupropion. Depending on individual sensitivity of the patient at addition to therapy of strong CYP2D6 inhibitors (for example a bupropiona, quinidine, fluoxetine, a paroksetin) it is possible to consider use of low doses of a vortioksetin.

At joint purpose of a vortioksetin after 6 days of use of a ketokonazol of 400 mg a day (CYP3A4/5 inhibitor and the R-glycoprotein) or a flukonazola of 200 mg in days (CYP2C9, CYP2C19 and CYP3A4/5 inhibitor) at healthy volunteers 5-fold increase in AUC of a vortioksetin was observed respectively 1,3 and 1. Dose adjustment is not required.

Influence of a single dose of 40 mg of an omeprazol (CYP2C19 inhibitor) on pharmacokinetics of prolonged use of a vortioksetin at healthy volunteers was not observed.

Combination of powerful CYP3A4 and CYP2C9 inhibitors at patients with low metabolism of CYP2D6 were not investigated, however it is probably necessary to expect the strengthened impact of a vortioksetin on such patients.

P450 cytochrome inductors. At single introduction of 20 mg of a vortioksetin jointly after 10 days of reception of rifampicin of 600 mg a day (the inductor CYP of isoenzymes) at healthy volunteers decrease in AUC of a vortioksetin by 72% was observed. Depending on individual reaction of the patient, dose adjustment can be required if the P450 cytochrome inductor is added to treatment vortioksetiny (for example rifampicin, carbamazepine, Phenytoinum).

Acetylsalicylic acid. Influence of repeated reception of acetylsalicylic acid of 150 mg a day on pharmacokinetics of a vortioksetin at healthy volunteers was not observed.

Influence of a vortioksetin on effect of other medicines. Anticoagulants and antiagregant. Essential effects of influence on indicators of the international normalized ratio, a prothrombin or R-/S-warfarin of plasma in comparison with placebo at joint introduction of a vortioksetin with the fixed warfarin dose at healthy volunteers were not observed. Besides, the significant inhibiting effect in comparison with placebo on aggregation of thrombocytes at joint administration of aspirin in a dose of 150 mg a day after reception of a vortioksetin at healthy volunteers was not observed. However, as well as at use of other serotonergic means, it is necessary to show care at use of a vortioksetin in combination with peroral anticoagulants or antiagregant in connection with potential increase in risk of bleeding from pharmakodinamichesky interactions.

Alcohol. Influence on pharmacokinetics of a vortioksetin or ethanol, and also essential disturbance of cognitive function in comparison with placebo after use of a vortioksetin in doses of 20 mg or 40 mg with simultaneous single administration of ethanol of 0,6 g/kg at healthy volunteers is not revealed. However, as other means operating on TsNS are not recommended to be applied вортиоксетин in combination with alcohol.

P450 cytochrome substrates. In vitro вортиоксетин did not show the potential of oppression or induction of isoenzymes of P450 cytochrome. The braking action of a vortioksetin on isoenzymes of P450 CYP2C19 cytochrome (омепразол, diazepam), CYP3A4/5 (ethinylestradiol, midazolam), CYP2B6 (бупропион), CYP2C9 (Tolbutamidum, S-warfarin), CYP1A2 (caffeine) or CYP2D6 (dextromethorphan) in healthy volunteers is revealed.

Considerable disturbance of cognitive function in comparison with placebo after use of a vortioksetin along with 10 mg of diazepam is not revealed.

The significant effect on levels of sex hormones in comparison with placebo after simultaneous use of a vortioksetin with the combined oral contraceptive (ethinylestradiol of 30 mkg / levonorgestrel of 150 mkg) is not revealed.

Lithium, tryptophane. Clinically significant effect of influence of stable concentration of lithium after simultaneous use with vortioksetiny for healthy volunteers was not observed. However there were messages on strengthening of effects at use of antidepressants serotonergic actions together with lithium or tryptophane therefore simultaneous use of a vortioksetin with these medicines should be carried out with care.

Contraindications:

Hypersensitivity to active ingredient or any component of drug.

Simultaneous use with the MAO (MAO) non-selective inhibitors or the MAO-A selection inhibitors.

Overdose:

Experience is limited. Reception of a vortioksetin in the range of doses from 40 to 75 mg caused a sharpening of such side effects: nausea, postural dizziness, diarrhea, abdominal discomfort, generalized itch, drowsiness and flush.

Treatment has to be symptomatic and include the corresponding monitoring. Medical observation in specialized conditions is recommended.

Storage conditions:

Does not demand special storage conditions. To store in the place, unavailable to children. A period of validity - 36 months.

Issue conditions:

According to the recipe

Packaging:

14 tablets in the blister, 2 blisters in a cardboard box.