Brintellix (Brintellix)

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Active substanceVortoxyxineVortoxyxine
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  • Brintellix
    pills inwards 
    H. Lundbeck A / S     Denmark
    • Dosage form: & nbspfilm coated tablets
    Composition:

    Active substance - vortioxetine hydrobromide 6,355 mg / 12,710 mg / 19,065 mg / 25,420 mg, equivalent to 5 mg / 10 mg / 15 mg / 20 mg vortioxetine.

    Excipients - mannitol 110.645 mg / 104.29 mg / 97.935 mg / 91.58 mg, microcrystalline cellulose 22.5 mg / 22.5 mg / 22.5 mg / 22.5 mg, giprolose 4.5 mg / 4.5 mg / 4.5 mg / 4.5 mg, sodium carboxymethyl starch (type A) 4.5 mg / 4.5 mg / 4.5 mg / 4.5 mg, magnesium stearate 1.5 mg / 1.5 mg / 1 , 5 mg / 1.5 mg.

    Film Sheath:

    for tablets 5 mg - Opadrai pink 4,5 mg (hypromellose 2,813 mg, titanium dioxide (E171) 1,375 mg, macrogol 400 0,281 mg, ferric oxide red oxide (E172) 0.032 mg);

    for tablets 10 mg - Opadrai yellow 4,5 mg (hypromellose 2,813 mg, titanium dioxide (E171) 1,350 mg, macrogol 400 0,281 mg, ferric oxide yellow oxide (E172) 0.056 mg);

    for tablets 15 mg - Opadrai orange 4.5 mg (hypromellose 2.813 mg, titanium dioxide (E171) 1.294 mg, macrogol 400 0.281 mg, iron dye oxide yellow (El72) 0.101 mg, iron dye red oxide (E172) 0.011 mg);

    for tablets 20 mg - Opadrai red 3.0 mg (hypromellose 1.875 mg, titanium dioxide (E171) 0.449 mg, macrogol 400 0.188 mg, ferric iron oxide red (E172) 0.488 mg).

    Description:

    5 mg: almond shaped tablet, covered with a pink film shell, embossed with "TL"on one side and" 5 "on the other.

    10 mg: tablets of almond-shaped form, coated with a film shell of light yellow color, embossed "TL" on one side and "10" on the other.

    15 mg: tablets of almond-shaped form, covered with a film shell of light orange color, embossed with "TL"on one side and" 15 "on the other.

    20 mg: almond shaped tablet, covered with a film coat of a brownish red color, embossed with "TL"on one side and" 20 "on the other.

    Pharmacotherapeutic group:Antidepressant
    ATX: & nbsp

    N.06.A.X.26   Vortoxyxine

    Pharmacodynamics:

    Mechanism of action

    The mechanism of action of vortioxetin appears to be related to its direct modulating serotonergic activity and inhibition of the serotonin transporter protein. Pre-clinical studies show that vortoxyxine acts as a 5-HT antagonist3, 5-HT7 and 5-HT1D receptor, partial agonist 5-HT1B receptors and a complete 5-HT agonist1A receptors, and also inhibits the 5-HT transporter, thereby modulating neurotransmission in several systems, primarily, serotonergic, but probably also noradrenergic, dopaminergic, neurotransmission mediated by histamine, acetylcholine, GABA and glutamate. Such multimodal pharmacological activity appears to underlie antidepressant and anxiolytic properties of vortoxyxine, and also determines the improvement in cognitive functions, learning and memory observed in animal studies. However, since the individual contribution of each pharmacological target to the observed pharmacodynamic profile of vortioxetin remains unclear, extrapolation of the preclinical data to humans should be done with caution.

    In two studies using positron emission tomography (PET) in humans to quantify the degree of occupancy of 5-HT carriers (using ligands 11C-MADAM or 11C-DASB), at a different dosing level of vortoxyxine, the following data were obtained: the average number of 5-HT vector carriers associated with vortioxetin was approximately 50% at a dose of 5 mg / day, 65% at a dose of 10 mg / day, and increased to 80% with an increase in dose to 20 mg / day.

    Clinical efficacy and safety

    The efficacy and safety of vortioxetin has been studied in a number of clinical trials involving more than 6,700 patients, of which more than 3,700 patients participated in short-term (≤12 weeks) studies with major depressive disorder (BDR).Twelve double-blind, placebo-controlled, 6/8 week, fixed-dose studies were conducted to determine the short-term efficacy of vortioxetine in BDR in adult patients (including elderly patients). The efficacy of vortioxetin was demonstrated, at least in the group with a single dose, in 9 of 12 studies, showing a change of at least 2 points from placebo on the Montgomery-Asberg Depression Scale (MADRS) and Hamilton (HAM-D24). This was clinically confirmed by the number of patients who responded to therapy and achieved remission, as well as an improvement in the scale of the overall clinical impression (CGI-I). The efficacy of vortioxetin increased with increasing doses. The effectiveness of individual studies is confirmed by meta-analysis (MMRM) average changes in the total score on a scale MADRS at 6/8 weeks in short-term placebo-controlled studies in adults. According to the results of the meta-analysis of these studies, the differences from placebo were statistically significant: -2.3 points (p = 0.007); -3.6 points (p <0.001); -4.6 points (p <0.001) at doses of 5, 10 and 20 mg / day, respectively, at a dose of 15 mg / day, statistically significant differences with placebo were not achieved by meta-analysis, but the mean differences compared with placebo were -2.6 points.The efficacy of vortioxetin is also confirmed in the composite analysis, in which the percentage of responders was 46% to 49% when vortoxyxine was used, compared to 34% for placebo (p <0.01; NRI).

    Besides, vortoxyxine in the dose range 5-20 mg / day demonstrated efficacy for a wide range of symptoms of depression (estimated by the change in scores for all individual subscales MADRS). The efficacy of vortioxetine at doses of 10 or 20 mg / day was also shown in a 12-week, double-blind, variable-dose comparative study with agomelatine at doses of 25 or 50 mg / day in patients with BDR. Vortoxyxine demonstrated a statistically significant superiority over agomelatine on a general scale score MADRS, which was clinically significant in the number of patients who responded to therapy, who achieved remission and improved on a scale CGI-I.

    Supportive therapy

    The persistence of antidepressant effect in maintenance therapy is shown in the study on the prevention of relapses. Patients, who were in remission after initial therapy with vortioxetine during a 12-week open-label study,were randomized to vortoxyxetin 5 mg or 10 mg / day or placebo and were observed for relapse during a double-blind observation period of at least 24 weeks (24 to 64 weeks). Vortoxyxine excluding placebo (p = 0.004) according to the main evaluation criterion - the time elapsed before the recurrence of BDR, with a risk ratio of 2.0; this means that the risk of recurrence was twice as high in the placebo group as in the vortioxetin group.

    Elderly patients

    In a double-blind, placebo-controlled, 8-week, fixed-dose study in elderly patients with depression (≥65 years, n= 452, 156 of them were treated with vortioxetine) vortoxyxine in a dose of 5 mg / day was superior to placebo in assessing the total score on scales MADRS and HAM-D24. The difference between vortioxetine and placebo was 4.7 on a scale MADRS at the 8th week of therapy (analysis MMRM).

    Patients with severe depression or with depression and a high level of anxiety

    The efficacy of vortioxetine has also been demonstrated in patients with severe depression (initial total score on a scale MADRS ≥30) and in patients with depression with a concomitant high level of anxiety (baseline overall score on the NAM-A scale ≥20) in short-term studies of adult patients (mean difference from placebo on a scale MADRS at weeks 6 and 8 varied from 2.8 to 7.3 points and from 3.6 to 7.3 points respectively (analysis MMRM)). In a separate study in the elderly vortoxyxine showed its effectiveness in this group of patients.

    The persistence of antidepressant effect in this category of patients was also shown in a long-term study on the prevention of relapses.

    Effect of vortioxetine on the Digital Symbol Replacement Test (Digit Symbol Substitution Test, DSST), Assessment of the quality of basic life skills on the scale of the University of California, San Diego (UPSA) (objective indicators), as well as the number of points in the questionnaire to assess the subjective deficit (Perceived Deficits Questionnaire, PDQ) and the score in the questionnaire to assess cognitive and physical functioning (Cognitive and Physical Functioning Questionnaire, CPFQ) (subjective indicators)

    The efficacy of vortoxyxine (5-20 mg / day) in patients with BDR has been studied in two short-term placebo-controlled trials in adults and one in elderly patients.

    Vortoxyxine had a statistically significant effect on the Digital Symbol Replacement Test (DSST) compared with placebo, with Δ = from 1.75 (p = 0.019) to 4.26 (p <0.0001) in two studies in adults and Δ = 2.79 (p = 0.023) in a study in elderly patients. In the meta-analysis (ANCOVA, LOCF) average change from the number of correct characters in DSST compared with the baseline in all three studies vortoxyxine was different from placebo (p <0.05) with a standardized magnitude of 0.35. When adjusting for a change in MADRS the total number of points in the meta-analysis of the same studies showed that vortoxyxine was different from placebo (p <0.05) with a standardized effect of 0.24.

    One study evaluated the effect of vortioxetine on functional ability using the Basic Life Quality Assessment on the scale of the University of California, San Diego (UPSA). Vortoxyxine was statistically significantly different from placebo with a score of 8.0 for vortioxetin vs. 5.1 for placebo (p = 0.0003).

    In one study vortoxyxine was superior to placebo in terms of subjective measures measured using a questionnaire to assess subjective deficits, with results of -14.6 for vortioxetin and -10.5 for placebo (p = 0.002). Vortoxyxine did not differ from placebo in terms of subjective measures, measured using a questionnaire to assess cognitive and physical functioning, with a score of -8.1 for vortoxy-toxin versus -6.9 for placebo (p = 0.086).

    Portability and safety

    Safety and tolerability of vortioxetin were established in the course of short-term and long-term studies in the dose range from 5 to 20 mg / day. Information on unwanted adverse reactions is provided in the "Side effect" section.

    Vortoxyxine did not increase the incidence of insomnia or drowsiness compared with placebo.

    Short-term and long-term placebo-controlled clinical trials consistently evaluated the possible withdrawal symptoms after abrupt cessation of treatment with vortioxetine. There was no clinically significant difference from placebo in the incidence or quality of withdrawal symptoms after both short-term (6-12 weeks) and after long-term (24-64 weeks) therapy with vortioxetine.

    The frequency of spontaneous complaints of sexual unwanted adverse reactions was low and similar to placebo, both in the short-term and in the long-term studies of vortioxetine. In studies using the Arizona scale of sexual function (ASEX) The incidence of sexual dysfunction caused by therapy, (TESD) and the total score on the scale ASEX clinically significant did not differ from placebo in the use of vortoxyxine in doses of 5-15 mg / day.When vortoxyxine was used at a dose of 20 mg / day, there was an increase in the incidence of sexual dysfunction compared with placebo (difference in frequency 14.2%, DP 95% (1.4, 27.0)).

    In the course of short-term and long-term studies vortoxyxine in comparison with placebo did not affect body weight, heart rate or blood pressure.

    Vortoxyxine had no clinically significant effect on liver and kidney function parameters in clinical trials.

    In patients with BDR vortoxyxine had no clinically significant effect on ECG parameters, including intervals QT, QTc, PR and QRS. With careful examination of the interval QTc in healthy subjects vortoxyxine in doses up to 40 mg / day did not affect its duration.

    Pharmacokinetics:

    Suction

    Vortoxyxine is slowly but well absorbed after oral administration. The maximum plasma concentration is achieved in 7-11 h. After repeated use in doses of 5, 10 or 20 mg / day, the average maximum plasma concentration (CmOh) is 9-33 ng / ml. Absolute bioavailability is 75%. The ingestion of food does not affect the pharmacokinetics of the drug (see section "Method of administration and dose").

    Distribution

    Average volume of distribution (Vss) is 2600 liters, which indicates an extensive extravascular distribution. The degree of binding to plasma proteins is high (98-99%) and, apparently, does not depend on the concentration of vortioxetin in the plasma.

    Biotransformation

    Vortoxyxine is extensively metabolized in the liver, mainly by oxidation with the help of isoenzyme CYP2D6 and to a lesser extent isoenzymes CYP3A4/5 and CYP2C9 and subsequent conjugation with glucuronic acid.

    In studies of drug interaction, there was no inhibitory or inducing effect of vortioxetine on isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5 (see section "Interaction with other drugs"). Vortoxyxine is a weak inhibitor and substrate of P-glycoprotein.

    The main metabolite of vortioxetin is pharmacologically inactive.

    Excretion

    The average half-life and oral clearance are 66 h and 33 l / h, respectively. About 2/3 of the inactive metabolite of vortioxetin is excreted in the urine and about 1/3 with feces. Only a small amount of vortioxetin is excreted with feces unchanged. Equilibrium plasma concentration is achieved in about 2 weeks.

    Linearity / nonlinearity

    Pharmacokinetics is linear and does not depend on time in the studied range of doses (2.5-60 mg / day).

    In accordance with the half-life on the basis of AUC0-24h after repeated doses of 5-20 mg / day, the accumulation index is from 5 to 6.

    Special patient groups

    Elderly patients

    In elderly healthy subjects (≥65 years; n= 20), the exposure of vortioxetin increased by 27% (CmOh and AUC) in comparison with the control group of young healthy subjects (≤45 years) after the administration of multiple doses of 10 mg / day. The minimum effective dose of vortioxetine 5 mg / day should always be used as an initial dose in patients ≥65 years of age (see section "Method of administration and dose"). It is necessary to carefully appoint elderly patients vortoxyxine in a dose above 10 mg / day (see section "Special instructions").

    Renal insufficiency

    After a single dose of vortoxyxine, 10 mg renal failure, estimated by the Cockcroft-Gault formula (mild, moderate or severe; n=8 in the group) resulted in a moderate (up to 30%) increase in vortioxetin exposure in comparison with the control group of healthy subjects. In patients with end-stage renal disease, dialysis resulted in only a slight decrease in exposure (AUC and CmOh decreased by 13% and 27%, respectively; n= 8) after a single dose of vortioxetin 10 mg. Correction of the dose is not required (see section "Special instructions").

    Liver failure

    After a single dose of vortoxyxine, 10 mg in patients with mild or moderate hepatic insufficiency (Child-Pugh A or B criteria; n= 8 in the group) no change in the pharmacokinetics of vortoxyxine was observed (change AUC less than 10%). Correction of the dose is not required (see section "Method of administration and dose"). Vortoxyxine It has not been studied in patients with severe hepatic insufficiency, so use the drug in such patients with caution (see section "Special instructions").

    Types of isoenzyme genes CYP2D6

    The plasma concentration of vortoxyxine was approximately twice as high in patients with reduced metabolic activity of the isoenzyme CYP2D6 in comparison with extensive metabolizers. Simultaneous application of strong inhibitors of isoenzymes CYP3A4/2C9 in patients with reduced metabolic activity of the isoenzyme CYP2D6 can potentially lead to an increase in the exposure of vortioxetin (see section "Interaction with other drugs"). In patients with extremely fast isoenzyme metabolism CYP2D6 plasma concentration of vortioxetine 10 mg / day was within the limits of values ​​obtained from extensive metabolizers at doses of 5 mg / day and 10 mg / day. As for all patients, depending on the individual reaction, consideration should be given to adjusting the dose of the drug (see section "Method of administration and dose").

    Pre-clinical safety data

    In studies of general toxicity, the administration of vortioxetine in mice, rats and dogs was accompanied by effects mainly from the CNS, which included such manifestations as salivation (rats and dogs), pupil dilations (dogs), and two episodes of seizures in dogs. When the drug was administered at the maximum recommended therapeutic dose of 20 mg / day, there was no seizure activity, given that the safety margin was determined at 5%. Organ toxicity was limited to the kidneys (rats) and liver (mice and rats).

    Changes in the kidneys in rats (glomerulonephritis, tubular obstruction, crystals in the renal tubules) and liver in mice and rats (hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, crystals in the bile ducts) were observed at exposure more than 2 times (rats) and 10 times (mice) exceeding human at the recommended maximum dose of 20 mg / day.These cases were mainly related to rodent-specific obstruction by the crystals of the renal tubules and bile ducts and are considered unlikely for humans.

    Vortoxyxine did not act genotoxically in a standard battery of tests in vitro and in vivo.

    Based on the results of standard biennial carcinogenicity studies in mice or rats vortoxyxine does not have a risk of carcinogenicity in humans.

    Vortoxyxine had no effect on fertility, the ability to mate, the function of the reproductive organs, or the morphology and motility of spermatozoa in rats. Vortoxyxine had no teratogenic effect in rats or rabbits, although the effect on fetal weight and ossification was noted in rats with exposure to doses of vortoxyxine exceeding 10 times the maximum daily dose for humans 20 mg / day. Similar effects were observed in rabbits with sub-therapeutic exposure.

    In pre- and postnatal studies in rats, the use of vortioxetine in doses that did not exert a toxic effect on the mother and corresponded to a dose of 20 mg / day in humans was associated with increased mortality of the young,a decrease in the rate of weight gain and a slowdown in their development (see the section on "Application during pregnancy and during breastfeeding").

    Vortoxyxetin penetrated the milk of lactating rats (see the section on "Application during pregnancy and during breastfeeding").

    In studies of juvenile toxicity in rats, the obtained data on the therapy with vortioxetin correlated with those obtained in adult animals.

    The active substance vortioxetine hydrobromide is classified as a PBT substance (persistent, bioaccumulative and toxic, risk to fish). However, in recommended doses to patients vortoxyxine represents a minor risk to the aquatic and terrestrial environment.

    Indications:

    Brintellix is ​​indicated for the treatment of major depressive episodes in adults.

    Contraindications:

    Hypersensitivity to the active substance or any component of the drug.

    Simultaneous use with nonselective monoamine oxidase (MAOI) inhibitors or with selective MAO A inhibitors (see section "Interaction with other drugs").

    Children and adolescents under 18 years of age (safety and efficacy not established).

    Carefully:

    Severe renal and hepatic insufficiency; mania and hypomania; pharmacologically uncontrolled epilepsy, convulsive fits in the anamnesis; pronounced suicidal behavior; cirrhosis of the liver; tendency to bleeding; simultaneous administration with MAO B inhibitors (selegiline, rasagiline); serotonergic drugs; drugs that reduce the threshold of convulsive readiness; lithium, tryptophan; medicinal preparations containing St. John's wort; oral anticoagulants and drugs that affect platelet function; drugs that can cause hyponatraemia; electroconvulsive therapy; elderly age.

    Pregnancy and lactation:

    Pregnancy

    Data on the use of vortioxetine in pregnant women are limited. Studies in animals have revealed reproductive toxicity of vortioxetine (see section "Pharmacological properties").

    In newborns whose mothers receive serotonergic drugs in late pregnancy, the following symptoms can occur: respiratory distress, cyanosis, apnea, seizures, temperature instability, difficulty in eating, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, increased nervous reflex excitability, irritability, lethargic sleep, constant crying, drowsiness and poor sleep. These symptoms can be associated with both withdrawal syndrome and excessive serotonergic activity. In most cases, such complications begin immediately or soon (<24 hours) after birth.

    Data from epidemiological studies suggest that the use of SSRIs during pregnancy, especially in later life, may increase the risk of developing pulmonary hypertension in newborns (PPHN). Although to date, the possibility of the relationship of this state with the use of vortioxetine has not been studied, taking into account the mechanism of its action (increasing serotonin concentration), the possible risk can not be ruled out.

    Brintellix should not be used during pregnancy unless the woman's clinical condition requires it.

    Lactation

    Available pharmacodynamic and toxicological data in animals have shown that vortoxyxine and its metabolites penetrate into breast milk. Probably, vortoxyxine also penetrates into breast milk in humans (see section "Pharmacological properties").

    The risk to the child during breastfeeding can not be ruled out.

    The decision to terminate breastfeeding or abstain from applying Brintellix should be made taking into account the assessment of the relative benefits of breastfeeding for the baby and the need for therapy for the mother.

    Fertility

    Fertility studies in male and female rats showed that vortoxyxine does not affect fertility, semen quality, or mating ability (see section "Pharmacological properties"). The use of drugs in a person belonging to the corresponding pharmacological class of antidepressants (SSRIs) has shown an effect on the quality of sperm, which is reversible. Influence on fertility of the person for the present moment was not observed.

    Dosing and Administration:

    Dosing regimen

    The initial and recommended dose of Brintellix in adults younger than 65 years is 10 mg once a day.Depending on the patient's individual response, the daily dose may be increased to a maximum dose of 20 mg vortoxyxine once a day or reduced to a minimum dose of 5 mg vortioxetin once a day.

    After completely resolving the symptoms of depression, it is recommended to continue treatment for at least 6 months to fix the antidepressant effect.

    Discontinuation of treatment

    Patients receiving treatment with Brintellix can immediately stop taking it without the need for a gradual dose reduction (see section "Pharmacological properties").

    Special patient groups

    Elderly patients

    In patients> 65 years of age, the minimum effective dose of Brintellix 5 mg once a day should always be used as the initial dose. Caution should be exercised in the treatment of patients ≥65 years of age using doses above 10 mg vortioxetine once daily, as the data on the use of the drug in this group of patients is limited (see section "Special instructions").

    Inhibitors of cytochrome P450

    Depending on the individual response of the patient, a reduction in the Brintellix dose may be required in the case of adherence to therapy with strong isoenzyme inhibitors CYP2D6 (for example, bupropion, quinidine, fluoxetine, paroxetine) (see.section "Interaction with other drugs").

    Inductors of cytochrome P450

    Depending on the patient's individual response, a dose adjustment of Brintellix may be required in the case of adherence to a wide range of cytochrome P450 inducers (for example rifampicin, carbamazepine, phenytoin) (see section "Interaction with other drugs").

    Children and teenagers (under the age of 18)

    The safety and efficacy of Brintellix in children and adolescents under the age of 18 years is not established. There are no data on this group of patients (see section "Special instructions").

    Mode of application

    Brintellix is ​​intended for oral administration. Film-coated tablets can be taken regardless of food intake.

    Side effects:

    Summary profile of the security profile

    The most common adverse reaction was nausea. Undesirable reactions were usually mild or moderate and were noted only during the first two weeks of treatment. Unwanted reactions were usually temporary and, in general, were not the cause of drug withdrawal. Unwanted adverse reactions from the gastrointestinal tract,such as nausea, were more common in women than in men.

    List of unwanted reactions in the form of a table

    The undesirable reactions listed below are distributed in frequency as follows: very often (≥1 / 10); often (from ≥1 / 100 to <1/10); infrequently (from ≥1 / 1000 to <1/100); rarely (from ≥1 / 10000 to <1/1000); very rarely (<1/10000), the frequency is unknown (the frequency can not be estimated based on available data).

    Class of organ system

    Frequency

    Unwanted reaction

    Disorders of the psyche

    Often

    Unusual dreams

    Disturbances from the nervous system

    Often

    Dizziness

    Frequency unknown

    Serotonin syndrome

    Vascular disorders

    Infrequently

    Tides

    Infringements from

    gastrointestinal

    tract

    Often

    Nausea

    Often

    Diarrhea, constipation, vomiting

    Disturbances from the skin and subcutaneous tissues

    Often

    Itching, including generalized itching

    Infrequently

    Night sweats

    Description of individual adverse reactions

    Elderly patients

    For doses of vortioxetine 10 mg and higher once a day, the dropout rate was higher in patients aged ≥ 65 years.

    For doses of vortioxetine 20 mg once daily, cases of nausea and constipation were higher in patients <65 years of age (42% and 15%, respectively) compared with patients <65 years (27% and 4%respectively) (see section "Special instructions").

    Sexual dysfunction

    In clinical studies, sexual dysfunction was assessed using ASEX (Arizona scale of sexual function). Doses of 5 to 15 mg did not differ from placebo. However, taking a 20 mg dose of vortoxyxine was associated with an increased incidence of sexual dysfunction caused by therapy (TESD) (see section "Pharmacological properties").

    Class-specific effect

    Epidemiological studies, predominantly involving patients aged 50 years and older, showed the existence of an increased risk of bone fractures in patients taking medications related to the relevant pharmacological classes antidepressants (SSRIs and TCAs). The mechanism leading to this risk is unknown, as well as whether this risk refers to taking vortioxetine.

    Overdose:

    At present, there is only limited experience on overdose of vortioxetin.

    Symptoms

    Admission vortioxetine in a dose of 40 to 75 mg led to an increase in the following adverse reactions: nausea, postural dizziness, diarrhea, discomfort in the abdomen, generalized itching, drowsiness and hot flashes.

    Treatment

    In case of an overdose, it is necessary to establish observation of the patient and perform symptomatic treatment. It is also recommended to carry out follow-up medical supervision under specialized conditions.
    Interaction:

    Vortoxyxetin undergoes extensive metabolism in the liver, mainly due to oxidation catalyzed by the isoenzyme CYP2D6, and to a lesser extent isoenzymes CYP3A4/5 and CYP2C9 (see section "Pharmacological properties").

    Possible effects of other drugs on the pharmacological action of vortioxetin

    Irreversible non-selective MAO inhibitors

    Because of the risk of serotonergic syndrome vortoxyxine it is contraindicated to use in combination with irreversible non-selective MAO inhibitors. Vortoxyxine can be appointed no earlier than 14 days after the cancellation of irreversible non-selective MAO inhibitors.

    Vortoxyxine should be discontinued no less than 14 days before the onset of irreversible non-selective MAO inhibitors (see "Contraindications").

    Reversible selective inhibitors of MAO A (moclobemide)

    Simultaneous use of vortioxetine with reversible selective MAO A inhibitors, such as moclobemide, is contraindicated (see section "Contraindications"). In case of the proven need for simultaneous use, the drug to be added should be used in minimal doses and with careful clinical observation for the onset of serotonin syndrome (see section "Special instructions").

    Reversible non-selective MAO inhibitors (linezolid)

    Simultaneous use of vortoxyxine with a weak reversible nonselective MAO inhibitor, such as an antibiotic linezolid, is contraindicated (see section "Contraindications"). In case of the proven need for simultaneous use, the drug to be added should be used in minimal doses with careful clinical monitoring for the appearance of serotonin syndrome (see section "Special instructions").

    Irreversible selective inhibitors of MAO B (selegiline, rasagiline)

    Although the risk of serotonin syndrome with simultaneous use of vortoxyxine and selective MAO B inhibitors is lower,than with the simultaneous use of vortioxetin and selective MAO A inhibitors, the combined use of vortioxetin with irreversible MAO B inhibitors, such as selegiline or rasagiline should be carried out with care. In case of simultaneous use, careful monitoring of the patient for serotonin syndrome (see section "Special instructions") is necessary.

    Serotonergic drugs

    The simultaneous use of vortioxetine and other drugs with a serotonergic effect (eg tramadol, sumatriptan and other triptans) can lead to the development of serotonin syndrome (see section "Special instructions").

    St. John's wort perforated

    Simultaneous use of antidepressants with serotonergic effect with preparations containing St. John's Wort (Hypericum perforatum), can lead to an increase in the frequency occurrence of undesirable reactions, including serotonin syndrome (see section "Special instructions").

    Drugs that reduce the threshold of convulsive readiness

    Antidepressants with a serotonergic effect can reduce the threshold of convulsive readiness.Simultaneous use with drugs that reduce the threshold of convulsive readiness (for example, antidepressants (TCAs, SSRIs, SSRIs), neuroleptics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion, tramadol) should be carried out with caution (see section "Special instructions"). .

    ECT (electroconvulsive therapy)

    Currently, the clinical experience of simultaneous use of vortioxetin and ECT is absent, therefore, with this application, care must be taken.

    Inhibitor inhibitors CYP2D6

    In the case of the use of vortoxyxine in a dose of 10 mg / day simultaneously with bupropion (a strong inhibitor of the isoenzyme CYP2D6) in a dose of 150 mg twice a day for 14 days in healthy subjects, the exposure of vortioxetine (AUC) has increased in 2,3 times. Undesirable reactions were more often observed with the addition of bupropion to current therapy with vortioxetine than with the addition of vortioxetine to current therapy with bupropion. Depending on the individual reaction of the patient, when a strong inhibitor of isoenzyme is added to the current therapy with vortioxetine CYP2D6 (e.g., bupropion, quinidine, fluoxetine, paroxetine) should consider the possibility of reducing the dose of vortioxetin (see section "Method of administration and dose").

    Inhibitor inhibitors CYP3A4 and CYP2C9

    The addition of vortioxetine 6 days after the initiation of ketoconazole at a dose of 400 mg / day (inhibitor of isoenzymes CYP3A4/5 and P-glycoprotein) or 6 days after the onset of fluconazole administration at a dose of 200 mg / day (inhibitor of isoenzymes CYP2C9, CYP2C19 and CYP3A4/5) in healthy subjects exposure (AUC) vortioxetin increased by 1.3 and 1.5 times, respectively. Correction of the dose is not required.

    Interactions in patients with weak isoenzyme activity CYP2D6

    Special studies of the use of vortioxetin simultaneously with strong inhibitors of isoenzyme CYP3A4 (such as itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, conivaptan and many HIV protease inhibitors) and isoenzyme inhibitors CYP2C9 (such as fluconazole and amiodarone) in patients with reduced isoenzyme activity CYP2D6 (see the section "Pharmacological properties") was not performed, nevertheless it can be expected that in these patients such use will lead to a more pronounced exposure of vortioxetine compared to the moderate effect described above.Taking a single dose of omeprazole 40 mg (inhibitor of isoenzyme CYP2C19) on the background of repeated doses of vortioxetin did not change the pharmacokinetics of the latter in healthy subjects.

    Inductors of cytochrome P450

    When taking a single dose of vortioxetin 20 mg 10 days after the initiation of rifampicin at a dose of 600 mg / day (inducer isoenzymes CYP broad spectrum) healthy subjects exposure (AUC) vortioxetin decreased by 72%. Depending on the individual response of the patient, when adding a strong inducer of cytochrome P450 isoenzymes of a wide spectrum (for example, rifampicin, carbamazepine, phenytoin) to the current therapy with vortioxetine, consideration should be given to the possibility of correcting the dose of vortioxetin (see the section "Dosing and Administration").

    Alcohol

    With the simultaneous administration of single doses of vortoxyxine (20 mg and 40 mg) and ethanol (0.6 g / kg), healthy subjects did not exhibit changes in the pharmacokinetics of vortioxetine or ethanol and significant cognitive impairment compared with placebo. However, during therapy with antidepressants, alcohol intake is not recommended.

    Acetylsalicylic acid

    Multiple administration of acetylsalicylic acid at a dose of 150 mg / day did not change the pharmacokinetics of multiple doses of vortioxetine in healthy subjects.

    Potential effects of vortioxetin on the pharmacological action of other drugs

    Anticoagulants and antiplatelet agents

    There was no significant effect of vortioxetine compared with placebo on prothrombin parameters, the international normalized ratio (INR) or the ratio R-ZS-varfarin in blood plasma with simultaneous application of multiple doses of vortoxyxine with a fixed dose of warfarin in healthy subjects. Also, there was no significant inhibitory effect of vortioxetin on platelet aggregation and the pharmacokinetics of acetylsalicylic and salicylic acid in comparison with placebo with simultaneous use of acetylsalicylic acid at a dose of 150 mg / day after repeated doses of vortioxetine in healthy subjects. However, as with other serotonergic drugs, care should be taken when using vortoxyxine and oral anticoagulants or antiplatelet agents at the same time because of the potential risk of bleeding caused by pharmacodynamic interaction (see section "Special instructions").

    Substrates of cytochrome P450

    Research in vitro did not reveal in vortioxetine the ability to inhibit or induce isoenzymes of the cytochrome P450 system (see the section "Pharmacological properties").

    After applying multiple doses of vortioxetine in healthy subjects, its inhibitory effect on the activity of cytochrome P450 isoenzymes CYP2C19 (omeprazole, diazepam), CYP3A4/5 (ethinyl estradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (tolbutamide, S-varmarin), CYP1A2 (caffeine) or CYP2D6 (dextromethorphan).

    Pharmacodynamic interactions were also not observed. There was no significant cognitive impairment compared with placebo when vortioxetin was used in combination with a single dose of diazepam 10 mg. There was no significant effect of vortioxetine in comparison with placebo on the level of sex hormones after its use in combination with a combined oral contraceptive (ethinyl estradiol 30 μg + levonorgestrel 150 μg).

    Lithium, tryptophan

    In healthy subjects, there were no clinically significant changes in the simultaneous use of lithium and multiple doses of vortioxetine. Nevertheless, due to the fact,that cases of increasing the effect of serotonergic antidepressants with simultaneous use with lithium or tryptophan have been described, the use of vortioxetin in combination with these drugs should be carried out with caution.

    Special instructions:

    Use in children and adolescents under the age of 18 years

    Brintellix is ​​not recommended for depression therapy in patients under the age of 18, since the safety and efficacy of vortioxetine in this age group has not been established (see section "Dosing and Administration"). In clinical trials in children and adolescents receiving other antidepressants, suicidal behavior (suicide attempts and suicidal thoughts) and hostility (with a predominance of aggressive behavior, a tendency to confrontation and irritation) were more frequent compared with those who received a placebo.

    Suicide / suicidal thoughts or clinical worsening

    Depression is associated with an increased risk of suicidal thoughts, self-injury and suicide (suicidal behavior). This risk persists until a marked remission occurs.Since improvements may not be observed during the first few weeks of therapy or even a longer period of time, patients should be monitored continuously until their condition improves.

    General clinical practice shows that in the early stages of recovery may increase the risk of suicide.

    Patients with a history of suicidal behavior or patients with a significant level of meditation on suicidal topics prior to the commencement of treatment are more likely to be at risk of suicidal thoughts or suicide attempts, so they should be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants with adult patients with mental disorders showed that when using antidepressants in patients younger than 25, there is an increased risk of suicidal behavior compared with placebo.

    Patients need careful monitoring, especially for those who show a high suicide risk, especially at the beginning of treatment or when changing the dose of the drug. Patients (and their guardians) should be warned about the need to monitorsigns of any clinical deterioration, suicidal behavior and suicidal thoughts, as well as unusual changes in behavior, and the need for immediate medical attention in the event of such symptoms.

    Convulsive seizures

    There is a possible risk of developing seizures with the use of antidepressants. Therefore, Brintellix should be used with caution in patients with seizures in the anamnesis or in patients with unstable epilepsy (see section "Interaction with other drugs"). If seizures occur or their frequency increases, treatment with vortioxetin should be discontinued.

    Serotonin syndrome or malignant neuroleptic syndrome Serotonin syndrome (SS) or malignant neuroleptic syndrome (CNS) are potentially life-threatening conditions and can occur with the use of the Brintellix preparation. The risk of CC or ZNS increases when combined with serotonergic drugs (including triptans), drugs that affect serotonin metabolism (including MAOI), antipsychotics or other dopamine antagonists.Patients should be observed for the appearance of objective and subjective symptoms of the SS and ZNS (see the sections "Contraindications" and "Interaction with other drugs").

    Symptoms of serotonin syndrome include changes in the mental state (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, lability of blood pressure, hyperthermia), neuromuscular abnormalities (eg, hyperreflexia, coordination disorders) and / or gastrointestinal disorders, intestinal symptoms (eg, nausea, vomiting, diarrhea). In the event of such symptoms, Brintellics should immediately stop therapy and begin symptomatic treatment.

    Mania / Hypomania

    Brintellix should be used with caution in patients with episodes of mania / hypomania in an anamnesis. The drug should be discontinued when developing a manic condition.

    Closed-angle glaucoma

    The dilatation of the pupils, which occurs after taking many antidepressants, including Brintellix, can provoke an attack of angle-closure glaucoma in patients with an anatomically narrow angle of the anterior chamber of the eye who did not undergo peripheral iridectomy.

    Bleeding

    Against the background of serotonergic antidepressants (SSRIs, SNRIs) have been observed rare cases of bleeding disorders, such as ecchymosis, purpura, gastrointestinal and gynecological bleeding. The drug should be used with caution in patients taking anticoagulants and / or drugs that affect platelet function (for example, atypical antipsychotics, phenothiazines, most tricyclic antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetylsalicylic acid) (see "Interaction with other medicinal agents "), as well as in patients with a known tendency to bleeding / clotting disorders.

    Hyponatremia

    Against the background of the use of antidepressants with serotonergic effect (SSRIs, SNRIs) reported rare cases of hyponatremia, probably due to the syndrome of inappropriate secretion of antidiuretic hormone. Caution should be exercised when applying vortioksetina in patients of high risk groups such as elderly patients, patients with hepatic cirrhosis or patients concurrently treated with drugs that may induce hyponatremia.

    It should be possible to cancel Brintellix in patients with symptomatic hyponatraemia and conduct appropriate medical interventions aimed at correcting their condition.

    Elderly patients

    Data on the use of Brintellix in elderly patients with a large depressive episode are limited. Therefore, care should be taken when treating patients ≥65 years of age using doses of vortioxetine above 10 mg once a day (see the sections "Pharmacological properties" and "Side effects").

    Renal impairment

    There are only limited data on the use of the drug in patients with severe renal failure. Therefore, care should be taken when treating these patients (see section "Pharmacological properties").

    Dysfunction of the liver

    Vortoxyxetin has not been studied in patients with severe hepatic impairment, so in such patients the drug should be used with caution (see section "Pharmacological properties").

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

    Brintellix does not have or has very little effect on the ability to drive a car or machinery.However, patients should be careful when driving vehicles or when working with dangerous mechanisms, especially at the beginning of treatment with vortioxetine or when changing its dose.

    Form release / dosage:

    Tablets, film-coated, 5 mg, 10 mg, 15 mg and 20 mg.

    Packaging:

    For 14 tablets in a contour squeeze box (blister) made of PVC / PVDC and aluminum foil. 1 or 2 blisters with instructions for use in a cardboard bundle.

    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    4 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-003422
    Date of registration:21.01.2016
    Expiration Date:21.01.2021
    The owner of the registration certificate:H. Lundbeck A / SH. Lundbeck A / S Denmark
    Manufacturer: & nbsp
    Representation: & nbspLUNDBEK EXPORT A / C LUNDBEK EXPORT A / C Denmark
    Information update date: & nbsp24.02.2017
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