Brintellix pills 5mg №28

Composition

Description of the dosage form

Tablets 5 mg: almond-shaped, film-coated pink, embossed with "TL" on one side and "5" - on the other.
pills 10 mg: almond-shaped, film-coated light yellow in color, with embossed "TL" on one side and "10" - on the other.
pills 15 mg: almond-shaped, film-coated light orange in color, embossed with “TL” on one side and “15” - on the other.
pills 20 mg: almond-shaped, film-coated brownish-red, with embossed "TL" on one side and "20" - on the other.

Mechanism of action

- antidepressant.

Pharmacodynamics

Mechanism of action
The mechanism of action of vortioxetine appears to be related to its direct modulating serotonergic activity and inhibition of the serotonin carrier protein. Preclinical studies show that vortioxetine acts as a 5-HT antagonist.₃-, 5-HT₇- and 5-HT_1Dreceptors, partial agonist 5-HT_1Breceptors and full 5-HT agonist_1A-receptors, as well as inhibits 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 seems 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 vortioxetine remains unclear, extrapolation of the above preclinical data to humans should be carried out with caution.
In two studies using positron emission tomography in humans for the purpose of quantifying the degree of employment of 5-HT carriers (using ligands¹¹C-MADAM or¹¹C-DASB), with different levels of dosing of vortioxetine, the following data were obtained: the average number of 5-HT carriers associated with vortioxetine was approximately 50% at a dose of 5 mg / day, 65% at a dose of 10 mg / day and increased to 80% with increasing doses up to 20 mg / day.

Clinical efficacy and safety
The efficacy and safety of vortioxetine has been studied in a number of clinical studies that included more than 6,700 patients, of whom more than 3,700 patients participated in short-term (<12 weeks) studies in major depressive disorder (BDF). Twelve double-blind, placebo-controlled 6/8-week, in fixed doses, studies were conducted to determine the short-term efficacy of vortioxetine for MDD in adult patients (including the elderly).
Efficacy of vortioxetine was demonstrated at least in a single dose group in 9 of 12 studies, where a change of at least 2 points from placebo on the Montgomery-Asberg Depression Rating Scales (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 on the overall clinical impression scale (CGI-I). The efficacy of vortioxetine increased with increasing dose. The effectiveness of individual studies was confirmed by a meta-analysis (MMRM) of average changes in the overall MADRS score of 6/8 weeks in short-term placebo-controlled studies in adults.According to the results of a 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 according to a meta-analysis, but the average differences compared with placebo were -2.6 points. The efficacy of vortioxetine is also confirmed in a pivotal analysis, in which the percentage of responders ranged from 46 to 49% with vortioxetine, compared with 34% with 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 depressive symptoms (assessed by the change in scores across all individual MADRS bases). The efficacy of vortioxetine in doses of 10 or 20 mg / day has also been shown in a 12-week double-blind, with variable doses of a comparative study with agomelatine in doses of 25 or 50 mg / day in patients with MDD. Vortioxetine demonstrated a statistically significant superiority over agomelatine in terms of the overall MADRS scale, which was clinically significant in the number of patients who responded to therapy, who achieved remission and improvement on the CG1-I scale.
Supportive Therapy The persistence of an antidepressant effect with maintenance therapy is shown in a study on relapse prevention. Patients who were in remission after initial therapy with vortioxetine during the 12-week open study,were randomized to groups — vortioxetine 5 or 10 mg / day or placebo — and were monitored for relapses during the double-blind observation period, which was at least 24 weeks (from 24 to 64 weeks). Vortioxetine was superior to placebo (p = 0.004) by the main evaluation criterion — time elapsed before recurrence of MDD, with a risk ratio of 2; this means that the risk of recurrence was 2 times higher in the placebo group than in the vortioxetine 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), vortioxetine 5 mg / day was superior to placebo in assessing the overall score for MADRS and HAM-D scales₂₄. The difference between vortioxetine and placebo was 4.7 on the MADRS scale for the 8th week of treatment (MMRM analysis).
Patients with severe depression or depression and high levels of anxiety. Efficacy of vortioxetine was also demonstrated in patients with severe depression (baseline total MADRS score ≥30) and in patients with depression with a concomitant high level of anxiety (baseline grade HAM-A ≥20) in short-term studies of adult patients (mean difference MADRS placebo on the 6th and 8th weeks ranged from 2.8 to 7.3 and from 3.6 to 7.3, respectively (MMRM analysis). In a separate study of elderly vortioxetine showed its effectiveness in this group of patients.
The persistence of the antidepressant effect in this category of patients has also been shown in a long-term recurrence prevention study.
The impact 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 subjective deficit assessment questionnaire (Perceived Deficits Questionnaire, PDQ) and the number of points in the questionnaire for the assessment of cognitive and physical functioning (Cognitive and Physical Functioning Questionnaire, CPFQ) (subjective indicators). The efficacy of vortioxetine (at a dose of 5–20 mg / day) in patients with BDR was studied in two short-term placebo-controlled studies in adults and in one in elderly patients.
Vortioxetine had a statistically significant effect on DSST compared with placebo, with Δ = 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 a meta-analysis (ANCOVA, LOCF), the mean change from the number of correct characters in DSST compared to baseline in all three studies, vortioxetine differed from placebo (p <0.05) with a standardized effect size of 0.35. When adjusted for the change in MADRS, the total score in the meta-analysis of the same studies showed that vortioxetine differed from placebo (p <0.05) with a standardized effect value of 0.24. In one study, the effect of vortioxetine on functional abilities was assessed using UPSA. Vortioxetine was statistically significantly different from placebo with 8 points for vortioxetine versus 5.1 points for placebo (p = 0.0003).
In one study, vortioxetine was superior to placebo in subjective measures measured with PDQ, with results of -14.6 for vortioxetine and -10.5 for placebo (p = 0.002).Vortioxetine did not differ from placebo with respect to subjective measures measured using CPFQ, with results of -8.1 for vortioxetine versus -6.9 for placebo (p = 0.086).
Portability and safety. The safety and tolerability of vortioxetine were established in the course of short-term and long-term studies in the dose range from 5 to 20 mg / day.
Information on undesirable side reactions is presented in the section "Side Effects".
Vortioxetine did not increase the incidence of insomnia or drowsiness compared with placebo.
In the course of short-term and long-term placebo-controlled clinical trials, possible symptoms of withdrawal were consistently evaluated after abrupt discontinuation of treatment with vortioxetine. There was no clinically significant difference with placebo in the incidence or quality of withdrawal symptoms after both short-term (6-12 weeks) and long-term (24-64 weeks) treatment with vortioxetine.
The frequency of spontaneous complaints of unwanted sexual 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 overall score on the ASEX scale did not clinically significantly differ from placebo when using vortioxetine at doses of 5-15 mg / day. When using vortioxetine at a dose of 20 mg / day, an increase in the incidence of sexual dysfunctions was observed compared with placebo (the difference in frequency was 14.2%, CI 95% (1.4; 27)).
In the course of short-term and long-term studies, vortioxetine compared with placebo did not affect body weight, heart rate or blood pressure.
Vortioxetine did not have a clinically significant effect on the parameters of the functioning of the liver and kidneys in clinical studies. In patients with DMD, vortioxetine did not have a clinically significant effect on ECG parameters, including QT, QTc, PR, and QRS intervals. With a thorough study of the QTc interval in healthy subjects, vortioxetine at doses up to 40 mg / day did not affect its duration.

Pharmacokinetics

Suction. Vortioxetine is slowly but well absorbed after oral administration. T_max in plasma - 7-11 hours. After repeated use in doses of 5, 10 or 20 mg / day, the average plasma C_max makes 9-33 ng / ml. Absolute bioavailability is 75%. Eating does not affect the pharmacokinetics of the drug (see "Dosage and administration").

Distribution.
Medium V_ss is 2600 l, 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 vortioxetine in the plasma.

Biotransformation.
Vortioxetine is extensively metabolized in the liver mainly due to oxidation using the CYP2D6 isoenzyme and, to a lesser extent, CYP3A4 / 5 and CYP2C9 isoenzymes and subsequent conjugation with glucuronic acid.

In studies of drug interactions, no inhibitory or inducing effect of vortioxetine on the isoenzymes of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 / 5 was found (see "Interaction"). Vortioxetine is a weak inhibitor and substrate of P-gp.The main metabolite of vortioxetine is pharmacologically inactive.

Inference.
Average t_1/2 and oral clearance of 66 h and 33 l / h, respectively. About 2/3 of the inactive metabolite vortioxetine is excreted in the urine and about 1/3 in the feces. Only a small amount of vortioxetine is excreted unchanged in the feces. Plasma c_ss is reached in about 2 weeks.

Linearity / nonlinearity.
Pharmacokinetics is linear and does not depend on time in the studied dose range (2.5-60 mg / day).
According to t_1/2 based on AUC_0-24 after multiple doses of 5–20 mg / day, the accumulation index is between 5 and 6.

Special patient groups
Elderly patients.
In elderly healthy subjects (≥65 years; n = 20), the exposure of vortioxetine increased by 27% (C_max and AUC) compared with a control group of young healthy subjects (≤45 years) after administration of multiple doses of 10 mg / day. The minimum effective dose of 5 mg / day vortioxetine should always be used as an initial dose in patients aged ≥65 years (see “Dosage and administration”). It is necessary to appoint with care to elderly patients vortioxetine in a dose higher than 10 mg / day (see. "Special instructions").

Renal failure.
After a single dose of 10 mg vortioxetine, renal failure, as measured by Cockroft-Gault formula (mild, moderate or severe; n = 8 in the group), resulted in a moderate (up to 30%) increase in vortioxetine exposure compared to the control group of healthy subjects.In patients with end-stage renal disease, dialysis resulted in only a slight decrease in exposure (AUC and C_max decreased by 13 and 27%, respectively; n = 8) after a single dose of 10 mg vortioxetine. Dose adjustment is not required (see. "Special instructions").

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

Vortioxetine has not been studied in patients with severe hepatic insufficiency; therefore, it is necessary to use the drug in such patients with caution (see “Special Instructions”).
Types of CYP2D6 isoenzyme genes. The plasma concentration of vortioxetine was approximately 2 times higher in patients with reduced metabolic activity of the CYP2D6 isoenzyme compared with extensive metabolisers. The simultaneous use of strong inhibitors of CYP3A4 / 2C9 isoenzymes in patients with reduced metabolic activity of the CYP2D6 isoenzyme can potentially lead to an increase in the exposure of vortioxetine (see "Interaction"). In patients with an extremely rapid metabolism of the CYP2D6 isoenzyme, the plasma concentration of vortioxetine 10 mg / day was within the range of values ​​obtained from extensive metabolisers at doses of 5 and 10 mg / day. As for all patients, depending on the individual reaction, the possibility of dose adjustment of the drug should be considered (see “Dosage and administration”).

Preclinical safety data
In the course of general toxicity studies, 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), dilated pupils (dogs) and two episodes of convulsions in dogs. With the introduction of the drug in the maximum recommended therapeutic dose of 20 mg / day is not recorded convulsive activity, given the fact that the margin of safety is defined in 5%. Organ toxicity was limited to 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, hyperplasia of the bile ducts, crystals in the bile ducts) were observed during exposure more than 2 times (rats) and 10 times (mouse) exceeding the human in the maximum recommended dose of 20 mg / day. These cases were mainly associated with rodent-specific obstruction of crystals of the renal tubules and bile ducts and are considered unlikely for humans.
Vortioxetine did not have a genotoxic effect in a standard battery of in vitro and in vivo tests.
Based on the results of standard 2-year studies of carcinogenicity in mice or rats, vortioxetine does not have the risk of carcinogenicity in humans.
Vortioxetine did not affect fertility, mating ability, the function of the reproductive organs, or the morphology and motility of spermatozoa in rats.Vortioxetine did not exert a teratogenic effect on rats or rabbits, although the effect on fetal weight and delayed ossification was observed in rats with exposure doses of vortioxetine 10 times more than the maximum daily dose for humans 20 mg / day. Similar effects were observed in rabbits with subtherapeutic exposure.
In pre- and postnatal studies in rats, the use of vortioxetine in doses that did not have a toxic effect on the mother and the corresponding dose of 20 mg / day in humans was associated with increased mortality of the young, a decrease in the rate of weight gain and slower development (see. pregnancy and breastfeeding ”).
Vortioxetine penetrated the milk of lactating rats (see “Use in pregnancy and lactation”).
In studies of juvenile toxicity in rats, the data obtained on treatment with vortioxetine correlated with those obtained in adult animals. The active ingredient vortioxetine hydrobromide is classified as a persistent, bioaccumulative and toxic substance (PBT substance; risk to fish). However, in the doses recommended by patients, vortioxetine represents a minor risk for the aquatic and terrestrial environment.
Indications of the drug Brintelliks
Major depressive episodes in adults (treatment).

Contraindications

hypersensitivity to the active substance or any component of the drug;
simultaneous use with non-selective monoamine oxidase inhibitors (MAOIs) or selective MAOIs A (see"Interaction");
children and adolescents under 18 years of age (safety and efficacy not established).
With care: severe renal and hepatic failure; mania and hypomania; pharmacologically uncontrolled epilepsy, history of convulsive seizures; pronounced suicidal behavior; cirrhosis of the liver; bleeding tendency; concomitant use with MAO B inhibitors (selegilin, rasagiline), serotonergic drugs, drugs that lower the threshold of seizure readiness, lithium, tryptophan, drugs that contain St. John's wort, perforated, oral anticoagulants, drugs, affecting platelet therapy, and using the program using the same methods, using the same methods, and using the same program, and using the program with the help of this program., electroconvulsive therapy, advanced age.
Use during pregnancy and lactation
Data on the use of vortioxetine in pregnant women is limited. Animal studies have revealed reproductive toxicity of vortioxetine (see “Pharmacokinetics”). Newborns whose mothers receive serotonergic drugs in late pregnancy may experience the following symptoms: respiratory distress, cyanosis, apnea, convulsions, instability of temperature, difficulty in eating, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, increased nervous reflex excitability, irritability, lethargy, 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 h) after birth.
Epidemiological studies suggest that using SSRIs during pregnancy, especially in late periods, may increase the risk of developing pulmonary hypertension in the newborn (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 the concentration of serotonin), the possible risk cannot be excluded.
Brinetelex should not be used during pregnancy unless the clinical condition of the woman herself requires.
Available pharmacodynamic and toxicological data in animals have shown that vortioxetine and its metabolites pass into breast milk. Probably, vortioxetine also penetrates human breast milk (see “Pharmacokinetics”).
Breastfeeding risk can not be excluded.
The decision to discontinue breastfeeding or abstaining from Brintellix should be made taking into account an 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 vortioxetine does not affect fertility, sperm quality, or mating ability (see Pharmacoctnetics).Human use of drugs belonging to the appropriate pharmacological class of antidepressants (SSRIs) has shown an impact on the quality of sperm, which is reversible. The effect on human fertility has not yet been observed.

Side effects

Security Profile Summary
The most common adverse reaction was nausea. Adverse reactions were usually mild or moderate and were observed only during the first 2 weeks of treatment. Adverse reactions were usually temporary and, in general, were not the reason for drug withdrawal. Unwanted gastrointestinal adverse reactions, such as nausea, were more common in women than in men.
The adverse 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 cannot be estimated based on the available data).

Table
List of undesirable reactions

Description of individual unwanted reactions

Elderly patients. For doses of vortioxetine 10 mg and above 1 time per day, the dropout rate was higher in patients aged ≥65 years.
For the dose of vortioxetine 20 mg 1 time per day, the incidence of nausea and constipation was 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 assessed using ASEX. Doses from 5 to 15 mg did not show a difference from placebo. However, taking a dose of vortioxetine 20 mg was associated with an increase in the incidence rate (TESD) (see “Pharmacodynamics”).
Class-specific effect. Epidemiological studies, mainly involving patients aged 50 years and older, have shown an increased risk of bone fractures in patients taking medication belonging to the appropriate pharmacological classes of antidepressants (tricyclic (TCA) and SSRIs). The mechanism leading to this risk is unknown, and it is also unknown if this risk applies to vortioxetine.

Interaction

Vortioxetine undergoes extensive metabolism in the liver mainly due to oxidation catalyzed by the CYP2D6 isoenzyme and, to a lesser extent, by the CYP3A4 / 5 and CYP2C9 isoenzymes (see “Pharmacokinetics”).
Possible effect of other drugs on the pharmacological action of vortioxetine
Irreversible non-selective MAOIs. Due to the risk of serotonin syndrome, it is contraindicated to use vortioxetine in combination with irreversible non-selective MAOIs. Vortioxetine can be assigned no earlier than 14 days after the cancellation of irreversible non-selective MAOIs.
Vortioxetine must be canceled at least 14 days before the start of the use of irreversible non-selective MAOI (see "Contraindications").
Reversible selective MAOI A (moclobemide). The simultaneous use of vortoixetine with reversible selective MAOI, such as moclobemide, is contraindicated (see. "Contraindications"). In the case of a proven need for simultaneous use of the drug being added, it should be used in minimal doses and with careful clinical observation for the occurrence of serotonin syndrome (see “Special Instructions”).
Reversible non-selective MAOI (linezolid). Simultaneous use of a vortoksetin with poorly reversible non-selective MAOI, such as the antibiotic linezolid, is contraindicated (see. "Contraindications"). In the case of a proven need for simultaneous use, the drug to be administered should be used in minimal doses with careful clinical monitoring for the occurrence of serotonin syndrome (see "Special Instructions").
Irreversible selective MAOI B (selegilin, rasagiline). Although the risk of serotonin syndrome with simultaneous use of vortioxetine and selective MAOI lower,than with the simultaneous use of vortioxetine and selective MAOI A, the combined use of vortioxetine with irreversible MAOI B, such as selegiline or rasagiline should be carried out with caution. In the case of simultaneous use, careful monitoring of the patient for the occurrence of serotonin syndrome is necessary (see “Special Instructions”).
Serotonergic drugs. The simultaneous use of vortioxetine and other drugs with a serotonergic effect (for example, tramadol, Sumatriptan, and other triptans) can lead to the development of serotonin syndrome (see "Special Instructions").
Hypericum perforatum. The simultaneous use of antidepressants with a serotonergic effect with drugs containing St. John's wort (Hypericum perforatum), can 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 lower the threshold of convulsive readiness. Simultaneous use with drugs that reduce the threshold of convulsive readiness (for example, antidepressants (TCA, SIOZS, SIOZSN), neuroleptics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion, tramadol) should be administered with caution (see "Special instructions").
Electroconvulsive therapy (ECT). At present, there is no clinical experience with the simultaneous use of vortioxetine and ECT, so caution should be exercised with this use.
Inhibitors of the isoenzyme CYP2D6.In the case of the use of vortioxetine at a dose of 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 vortioxetine (AUC) increased 2.3 times. Adverse reactions were more frequently observed when bupropion was added to the current treatment with vortioxetine than when it was attached to the current treatment with bupropion. Depending on the patient's individual response, when a strong inhibitor of the CYP2D6 isoenzyme is added to current therapy with vortoxetine (for example, bupropion, quinidine, Fluoxetine, paroxetine), the possibility of reducing the dose of vortioxetine should be considered (see. "Dosage and administration").
Inhibitors of isoenzymes CYP3A4 and CYP2C9. Joining vortioxetine 6 days after the start of Ketoconazole at a dose of 400 mg / day (inhibitor of CYP3A4 / 5 and P-gp isoenzymes) or 6 days after starting the use of Fluconazole at a dose of 200 mg / day (inhibitor of CYP2C9, CYP2C19 and CYP3A4 / 5 isoenzymes ) in healthy subjects, the exposure (AUC) of vortioxetine increased 1.3 and 1.5 times, respectively. Dose adjustment is not required.

Interactions in patients with weak activity of the isoenzyme CYP2D6. Special studies on the use of vortioxetine at the same time as strong inhibitors of the CYP3A4 isoenzyme (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 decreased