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Instruction for use: Brintellix

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Dosage form: film coated tablets

Active substance: Vortioxetine*

ATX

N06AX26 Vortioxetine

Pharmacological groups:

Antidepressant [Antidepressants]

The nosological classification (ICD-10)

F32 Depressive episode: Adynamic subdepression; Astheno-adynamic subdepressive states; Asthenoadressive disorder; Astheno-depressive disorder; Asthenodepressive state; Astheno-depressive state; Major Depressive Disorder; Vyaloapatichesky depression with retardation; Double Depression; Depressive pseudodement; Depressive illness; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive disorders; Depressive syndrome; Depressive syndrome larviated; Depressive syndrome in psychoses; Depressed masks; Depression; Depression Depletion; Depression with the phenomena of inhibition within the framework of cyclothymia; Depression is smiling; Involutional depression; Involutionary melancholy; Involutional depression; Manic-depressive disorder; Masked Depression; Melancholic Attack; Neurotic depression; Neurotic depression; Shallow Depression; Organic depression; Organic depressive syndrome; Simple depression; Simple melancholic syndrome; Psychogenic depression; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Reactive depression; Recurrent depression; Seasonal depressive syndrome; Severostatic depression; Senile Depression; Symptomatic Depression; Somatogenic depression; Cyclotymic depression; Exogenous depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome

F33 Recurrent depressive disorder: Major depressive disorder; Secondary depression; Double Depression; Depressive pseudodement; Depressive mood disorder; Depressive disorder; Depressive mood disorder; Depressive state; Depressive syndrome; Depressed masks; Depression; Depression is smiling; Involutional depression; Involutional depression; Masked Depression; Melancholic Attack; Reactive depression; Reactive depression with moderate psychopathological symptoms; Reactive depressive states; Exogenous depression; Endogenous depression; Endogenous Depressive Conditions; Endogenous Depression; Endogenous depressive syndrome

Composition

Tablets covered with a film membrane 1 tab.

active substance:

vortioxetine hydrobromide 6,355 / 12.71 (19.065) 25.42 mg

is equivalent to 5/10/15/20 mg vortioxetine

auxiliary substances: mannitol - 110.645 / 104.29 / 97.935 / 91.58 mg; MCC - 22.5 / 22.5 / 22.5 / 22.5 mg; giprolose - 4,5 / 4,5 / 4,5 / 4,5 mg; sodium carboxymethyl starch (type A) 4.5 / 4.5 / 4.5 / 4.5 mg; magnesium stearate 1.5 / 1.5 / 1.5 / 1.5 mg

film sheath

for table. 5 mg: Opadry pink (hypromellose - 2,813 mg, titanium dioxide (E171) - 1,375 mg, macrogol 400 - 0,281 mg, ferric iron oxide red (E172) - 0.032 mg) 4.5 mg

for table. 10 mg: Opadry yellow (hypromellose - 2,813 mg, titanium dioxide (E171) - 1.35 mg, macrogol 400 - 0.281 mg, ferric oxide yellow oxide (E172) - 0.056 mg) 4.5 mg

for table. 15 mg: Opadry orange (hypromellose - 2,813 mg, titanium dioxide (E171) - 1,294 mg, macrogol 400 - 0,281 mg, ferric oxide yellow oxide (E172) - 0.101 mg, iron oxide red oxide (E172) 0.011 mg) - 4 , 5 mg

for table. 20 mg: Opadry red (hypromellose - 1,875 mg, titanium dioxide (E171) - 0,449 mg, macrogol 400 - 0,188 mg, iron oxide red oxide (E172) - 0.488 mg) - 3 mg

Description of dosage form

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

Tablets 10 mg: almond shaped, covered with a film coating of light yellow color, embossed with "TL" on one side and "10" on the other.

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

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

Pharmachologic effect

Mode of action - antidepressant.

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 transfer protein. Preclinical studies show that vortioxetin acts as an antagonist of 5-HT3-, 5-HT7- and 5-HT1D-receptors, a partial agonist of 5-HT1B receptors and a complete 5-HT1A receptor agonist, 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 the antidepressant and anxiolytic properties of vortioxetine, 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 carried out with caution.

In two studies using positron emission tomography in humans to quantify the degree of occupancy of 5-HT carriers (using ligands 11C-MADAM or 11C-DASB), at different levels of dosing of vortioxetin, the following data were obtained: the average number of carriers of 5-HT, 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 the dose to 20 mg / day.

Clinical efficacy and safety

The efficacy and safety of vortioxetin have 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 the elderly).

The efficacy of vortoxyxine was demonstrated in at least one dose group in 9 out of 12 studies, showing a change of at least 2 points from placebo on the Montgomery-Asberg Depression Scale (MADRS) and Hamilton (HAM-D24) scales. 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 was confirmed by a meta-analysis (MMRM) of the mean changes in the total score on the MADRS scale 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 a composite analysis, in which the percentage of responders was 46 to 49% when vortoxyxine was used, compared with 34% for placebo (p <0.01, NRI analysis).

In addition, vortioxetine in the dose range of 5-20 mg / day demonstrated efficacy against a wide range of symptoms of depression (estimated by the change in scores for all individual subscales of 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 statistically significant superiority over agomelatine in the overall score of the MADRS scale, which was clinically significant in the number of patients responding to therapy who achieved remission and improvement on the CG1-I scale.

Supportive therapy. The persistence of antidepressant effect in maintenance therapy is shown in the study on the prevention of relapses. Patients who were remission after initial therapy with vortoxyxine during a 12-week open-label study were randomized to vortioxetin 5 or 10 mg / day or placebo and were observed for relapse during the double-blind observation period, which was at least 24 weeks (from 24 to 64 weeks). Vortoxyxine exceeded placebo (p = 0.004) according to the main evaluation criterion - the time elapsed before the relapse of BDR, with a risk ratio of 2; this means that the risk of recurrence was 2-fold higher in the placebo group than 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 whom received vortoxyxine treatment), vortioxetine 5 mg / day was superior to placebo in assessing the overall score for the MADRS and HAM-D24 scales. The difference between vortioxetine and placebo was 4.7 on the MADRS scale for the 8th week of therapy (MMRM analysis).

Patients with severe depression or depression and a high level of anxiety. The efficacy of vortioxetine has also been demonstrated in patients with severe depression (baseline MADRS score ≥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 the MADRS scale for weeks 6 and 8 varied from 2.8 to 7.3 points and from 3.6 to 7.3 points respectively (MMRM analysis)). In a separate study in the elderly, vortioxetin also showed efficacy 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.

The effect of vortioxetine on the Digit Symbol Substitution Test (DSST), the 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 for assessing subjective deficits (Perceived Deficits Questionnaire , PDQ) and the score in the Cognitive and Physical Functioning Questionnaire (CPFQ) questionnaire (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 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) of the mean change from the number of correct symbols in DSST compared to the baseline in all three studies, vortioxetin was different from placebo (p <0.05) with a standardized magnitude of 0.35. When adjusting for a change in MADRS, the total score 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 capacity with UPSA. Vortoxyxine was statistically significantly different from placebo with a score of 8 for vortioxetine vs. 5.1 for placebo (p = 0.0003).

In one study, vortioxetine was superior to placebo in terms of subjective measures measured with PDQ, with results of -14.6 for vortioxetine and -10.5 for placebo (p = 0.002). Vortoxyxetin did not differ from placebo in terms of subjective measures measured with CPFQ, with a result of -8.1 for vortioxetine 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 effects" 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 possible withdrawal symptoms after abrupt cessation of treatment with vortioxetine. There was no clinically significant difference with placebo in the incidence or quality of withdrawal symptoms, either after a short-term (6-12 weeks) or after a 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 Sexual Function Scale (ASEX), the incidence of sexual dysfunction caused by therapy (TESD) and the overall ASEX score were clinically not significantly different from placebo when using vortoxyxetine at doses of 5-15 mg / day. When vortioxetine 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%, CI 95% (1.4, 27)).

In the course of short-term and long-term studies, vortioxetine, 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, vortioxetin did not have a clinically significant effect on ECG parameters, including QT, QTc, PR, and QRS intervals. With a careful study of the QTc interval 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. Tmax in plasma is 7-11 hours. After repeated use at doses of 5, 10 or 20 mg / day, the average plasma Cmax is 9-33 ng / ml. Absolute bioavailability is 75%. Eating does not affect the pharmacokinetics of the drug (see "Method of administration and dose").

Distribution. The average Vss is 2,600 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. Vortioxetine is extensively metabolized in the liver mainly by oxidation with the help of the CYP2D6 isoenzyme and, to a lesser extent, isoenzymes CYP3A4 / 5 and CYP2C9 and subsequent conjugation with glucuronic acid.

No inhibitory or inducing effects of vortioxetine on the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 / 5 were found in the drug interaction studies (see "Interaction"). Vortoxyxine is a weak inhibitor and substrate of P-gp. The main metabolite of vortioxetin is pharmacologically inactive.

Excretion. The average T1 / 2 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. Plasma Css 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).

According to T1 / 2, based on AUC0-24, after multiple doses of 5-20 mg / day, the accumulation index is 5 to 6.

Special patient groups

Elderly patients. In elderly healthy subjects (≥65 years, n = 20), the exposure of vortioxetin increased by 27% (Cmax 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 "Method of administration and dose"). It is necessary to carefully appoint elderly patients vortioxetine at a dose above 10 mg / day (see "Special instructions").

Renal failure. 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 compared to the control group of healthy subjects. In patients with terminal kidney disease, dialysis resulted in only a slight decrease in exposure (AUC and Cmax decreased by 13 and 27%, respectively, n = 8) after a single dose of vortioxetin 10 mg. Correction of the dose is not required (see "Special instructions").

Liver failure. After a single dose of vortoxyxine, 10 mg in patients with mild or moderate hepatic impairment (Child-Pugh A or B criteria, n = 8 in the group), no change in the pharmacokinetics of vortioxetin was observed (AUC change less than 10%). Correction of the dose is not required (see "Method of administration and dose").

Vortoxyxetin has not been studied in patients with severe hepatic impairment, so use the drug in such patients with caution (see "Special instructions").

Types of isoenzyme genes CYP2D6. Plasma concentration of vortoxyxine was approximately 2 times higher in patients with reduced metabolic activity of the CYP2D6 isoenzyme compared to extensive metabolizers. Simultaneous use of strong inhibitors of CYP3A4 / 2C9 isoenzymes in patients with reduced metabolic activity of the CYP2D6 isoenzyme may potentially lead to an increase in the exposure of vortioxetin (see "Interaction"). In patients with extremely rapid metabolism of the CYP2D6 isoenzyme, the plasma concentration of vortoxyxine 10 mg / day was within the limits of values obtained in extensive metabolizers at doses of 5 and 10 mg / day. As for all patients, depending on the individual reaction, consideration should be given to the possibility of dose adjustment (see "Method of administration and dose").

Pre-clinical safety data

In general toxicity studies, the administration of vortioxetine in mice, rats and dogs was accompanied by effects, mainly from the side of 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 renal function in rats (glomerulonephritis, tubular obstruction, crystals in the renal tubules) and liver in mice and rats (hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, bile duct crystals) 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 exert a genotoxic effect in a standard battery of tests in vitro and in vivo.

Based on the results of standard 2-year studies of carcinogenicity in mice or rats, vortioxetin does not have a risk of carcinogenicity in humans.

Vortoxyxetin did not affect fertility, the ability to mate, the function of the reproductive organs, or the morphology and motility of spermatozoa in rats. Vortoxyxetin did not have a teratogenic effect on rats or rabbits, although the effect on fetal weight and ossification was noted in rats when exposure to doses of vortoxyxine exceeded 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 vortoxyxine in doses that did not have 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 " pregnancy and lactation ").

Vortoxyxetin penetrated the milk of lactating rats (see "Application in pregnancy and lactation").

In studies of juvenile toxicity in rats, the obtained data on the therapy with vortioxetin correlated with those obtained in adult animals. The active ingredient vortioxetine hydrobromide is classified as persistent, bioaccumulative and toxic substance (SBT substance, risk for fish). However, in recommended doses, vortioxetin poses little risk to the aquatic and terrestrial environment.

Indications for Brintellix

Major depressive episodes in adults (treatment).

Contraindications

hypersensitivity to the active substance or to any component of the drug;

simultaneous use with nonselective monoamine oxidase (MAOI) inhibitors or selective MAOI A (see "Interaction");

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

With caution: 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, drugs containing St. John's wort, oral anticoagulants and drugs that affect platelet function, drugs that can cause hyponatremia , electroconvulsive therapy, advanced age.

Application in pregnancy and lactation

Data on the use of vortioxetine in pregnant women are limited. Studies in animals have revealed the reproductive toxicity of vortioxetine (see "Pharmacokinetics"). In newborns whose mothers receive serotonergic drugs in late pregnancy, the following symptoms may occur: respiratory distress, cyanosis, apnea, convulsions, temperature instability, difficulty eating, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, reflex excitability, irritability, lethargic sleep, constant crying, drowsiness and bad sleep. These symptoms can be associated with both withdrawal syndrome and excessive serotonergic activity. In most cases, such complications begin immediately or soon (<24 h) after birth.

Data from epidemiological studies suggest that the use of SSRIs during pregnancy, especially in later life, may increase the risk of developing persistent 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), a possible risk can not be ruled out.

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

Available pharmacodynamic and toxicological data in animals have shown that vortioxetin and its metabolites penetrate into breast milk. Probably, vortioxetin also enters the human breast milk (see "Pharmacokinetics").

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 have shown that vortioxetin does not affect fertility, sperm quality, or mating ability (see "Pharmacokinetics"). 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.

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 2 weeks of treatment. Unwanted reactions were usually temporary and, in general, were not the cause of drug withdrawal. Undesirable side reactions from the gastrointestinal tract, such as nausea, were more common in women than in men.

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).

Table

List of unwanted reactions

Body systems Frequency Unwanted reaction
Disorders of the psyche Often Unusual dreams
From the nervous system Often Dizziness
Frequency unknown Serotonin syndrome
From the side of the vessels Infrequently Tides
From the gastrointestinal tract Often Nausea
Often Diarrhea, constipation, vomiting
From the skin and subcutaneous tissues Body systems Often Itching, incl. generalized
Infrequently Night sweat

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 a dose of vortoxyxine 20 mg once a day, nausea and constipation were higher in patients aged ≥65 years (42% and 15%, respectively) compared with patients <65 years (27% and 4%, respectively) (see "Special instructions ").

Sexual dysfunction. In clinical studies, sexual dysfunction was evaluated using ASEX. 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 TESD (see Pharmacodynamics).

Class-specific effect. Epidemiological studies, predominantly involving patients aged 50 years and older, have shown an increased risk of bone fractures in patients taking medications related to the respective pharmacological classes of antidepressants (tricyclic (TCAs) and SSRIs). The mechanism leading to this risk is unknown, as well as it is not known whether this risk applies to taking vortioxetin.

Interaction

Vortoxyxetin is extensively metabolized in the liver mainly by oxidation catalyzed by the isoenzyme CYP2D6, and to a lesser extent by the isoenzymes CYP3A4 / 5 and CYP2C9 (see "Pharmacokinetics").

Possible effects of other drugs on the pharmacological action of vortioxetin

Irreversible non-selective MAOIs. Because of the risk of serotonergic syndrome, vortioxetin is contraindicated in combination with irreversible non-selective MAOIs. Vortoxyxetin can be prescribed no earlier than 14 days after the cancellation of irreversible non-selective MAOIs.

Vortoxyxetin must be discontinued no less than 14 days before the application of irreversible non-selective MAOIs (see "Contraindications").

Reversible selective MAOA A (moclobemide). The simultaneous use of vortioxetine with reversible selective MAO A, such as moclobemide, is contraindicated (see Contraindications). In the 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 appearance of serotonin syndrome (see "Special instructions").

Reversible nonselective MAOI (linezolid). The simultaneous use of vortioxetine with a weak reversible non-selective MAOI, such as the antibiotic linezolid, is contraindicated (see Contraindications). In the 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 "Special instructions").

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

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

Saint John's wort. Simultaneous use of antidepressants with serotonergic effect with preparations containing St. John's wort (Hypericum perforatum) may lead to an increase in the incidence of undesirable reactions, including serotonin syndrome (see "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), antipsychotics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion, tramadol) should be carried out with caution (see "Special instructions").

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

Inhibitors of the isoenzyme CYP2D6. In the case of vortoxyxine 10 mg / day simultaneously with bupropion (a strong inhibitor of the isoenzyme CYP2D6) at a dose of 150 mg twice a day for 14 days in healthy subjects, the exposure of vortioxetin (AUC) increased by 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 considering the use of a strong inhibitor of the isoenzyme CYP2D6 (eg, bupropion, quinidine, fluoxetine, paroxetine) in the current therapy with vortioxetin, the possibility of reducing the dose of vortioxetin should be considered (see "Method of administration and dose").

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

Interactions in patients with a weak activity of the isoenzyme CYP2D6. Special studies of the use of vortioxetin concurrently with strong inhibitors of the isoenzyme CYP3A4 (such as itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, conivaptan and many HIV protease inhibitors) and inhibitors of the CYP2C9 isoenzyme (such as fluconazole and amiodarone) in patients with reduced CYP2D6 isoenzyme activity , "Pharmacokinetics") was not performed, nevertheless it can be expected that in these patients such an application will lead to a more pronounced exposure of vortioxetin compared with moderate action , described above. The administration of a single dose of omeprazole 40 mg (inhibitor of the isoenzyme CYP2C19) against the background of repeated doses of vortioxetin did not change the pharmacokinetics of the latter in healthy subjects.

Inductors of cytochrome P450. When a single dose of vortioxetin 20 mg was administered 10 days after the initiation of rifampicin at a dose of 600 mg / day (the inductor of the broad spectrum CYP isoenzymes), the exposure (VUC) of vortioxetin decreased by 72% in healthy subjects. Depending on the individual reaction of the patient, the possibility of correcting the dose of vortioxetin should be considered when adding a strong inducer of cytochrome P450 isoenzymes of broad spectrum (eg rifampicin, carbamazepine, phenytoin) to current therapy with vortioxetine (see "Method of administration and dose").

Alcohol. At simultaneous administration of single doses of vortioxetine (20 and 40 mg) and ethanol (0.6 g / kg), healthy subjects did not observe changes in the pharmacokinetics of vortioxetine or ethanol and significant impairment of cognitive functions 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 antiaggregants. There was no significant effect of vortioxetine versus placebo on prothrombin parameters, MHO, or R- / S-warfarin ratio in blood plasma, while using multiple doses of vortoxyxine with a fixed dose of warfarin in healthy subjects. There was also 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 the use of other serotonergic drugs, caution should be exercised while using vortioxetine and oral anticoagulants or antiplatelet agents due to the potential risk of bleeding caused by pharmacodynamic interaction (see "Special instructions").

Substrates of cytochrome P450. In vitro studies have not revealed in vortioxetine the ability to inhibit or induce isoenzymes of the cytochrome P450 system (see "Pharmacokinetics"). After using multiple doses of vortioxetine in healthy subjects, its inhibitory effect on the activity of cytochrome P450 isoenzymes CYP2C19 (omeprazole, diazepam), CYP3A4 / 5 (ethinylestradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (tolbutamide, S-warfarin) 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 compared with placebo on the level of sex hormones after its use in combination with a combined oral contraceptive (ethinylestradiol 30 μg + levonorgestrel 150 μg).

Lithium, tryptophan. In healthy subjects, no clinically significant changes were observed with simultaneous use of lithium and multiple doses of vortioxetine. However, since the 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.

Dosing and Administration

Inside, regardless of food intake.

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

Termination of treatment. Patients treated with Brintellix can immediately stop taking it without the need for a gradual dose reduction (see Pharmacodynamics).

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. Care should be taken when treating patients ≥65 years of age using doses above 10 mg vortioxetin once daily, since data on the use of the drug in this group of patients are limited (see "Special instructions").

Inhibitors of cytochrome P450. Depending on the individual response of the patient, a reduction in the dose of Brintellix may be required if the therapy is joined by strong inhibitors of the CYP2D6 isoenzyme (eg, bupropion, quinidine, fluoxetine, paroxetine) (see "Interaction").

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 (eg, rifampicin, carbamazepine, phenytoin) (see "Interaction").

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

Overdose

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

Symptoms: ingestion of vortoxyxine in a dose of 40 to 75 mg led to an increase in the following adverse reactions: nausea, postural dizziness, diarrhea, abdominal discomfort, generalized pruritus, 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.

Special instructions

Use in children and adolescents under 18 years. Brintellix is not recommended for treatment of depression in patients under the age of 18, since the safety and efficacy of vortoxyxine in this age group has not been established (see "Method of administration and dose"). 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 impairment. Depression is associated with an increased risk of suicidal thoughts, self-injury and suicide (suicidal behavior). This risk persists until a marked remission occurs. Because the improvement 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 initiating 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 years there is an increased risk of suicidal behavior compared with placebo.

Patients should be closely monitored, 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 caregivers) should be warned about the need to monitor the signs of any clinical impairment, suicidal behavior and suicidal thoughts, and unusual behavioral changes, and seek medical help immediately if any such symptoms occur.

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 "Interaction"). If seizures occur or their frequency increases, treatment with vortioxetin should be discontinued.

Serotonin syndrome (SS) or malignant neuroleptic syndrome (CNS). MOP or ZNS are potentially life-threatening conditions and can occur when using 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 "Contraindications" and "Interaction").

Symptoms of SS 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 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. Dilation of pupils, which occurs after taking many antidepressants, incl. and 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 the use of serotonergic antidepressants (SSRIs, SSRIs), rare cases of hemorrhagic disorders such as ecchymosis, purpura, gastrointestinal and gynecological bleeding were noted. The drug should be used with caution in patients taking anticoagulants and / or drugs that affect platelet function (eg, atypical antipsychotics, phenothiazines, most TCAs, NSAIDs and acetylsalicylic acid) (see "Interaction"), 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, SSRIs), there were reported rare cases of hyponatremia, probably due to the syndrome of inadequate secretion of antidiuretic hormone. Caution should be exercised when using vortioxetine in patients from high-risk groups such as elderly patients, patients with cirrhosis of the liver, or patients who are simultaneously receiving therapy with drugs that can cause hyponatraemia. 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 daily (see "Pharmacokinetics" and "Side effects").

Impaired renal function. 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 "Pharmacokinetics").

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 "Pharmacokinetics").

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

Release form

Tablets, film-coated, 5 mg, 10 mg, 15 mg and 20 mg. According to Table 14. in a contour squeeze box (blister) made of PVC / PVDC and aluminum foil. 1 or 2 bl. placed in a cardboard box.

Conditions of leave from pharmacies

On prescription.

Storage conditions for Brintellix

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life of Brintellix

4 years.

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

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