Brintellix 10mg 28 tablets

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BRINTELLIX Trade name: BRINTELLIX International Nonproprietary Name: Vortioxetine. Dosage form: Film-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, hypromellose 4.5 mg/4.5 mg/4.5 mg/4.5 mg, sodium starch glycolate (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 / 1.5 mg. Film coating: For 5 mg tablets - Opadry Pink 4.5 mg (hypromellose 2.813 mg, titanium dioxide (E171) 1.375 mg, macrogol 400 0.281 mg, iron oxide red colorant (E172) 0.032 mg); For 10 mg tablets - Opadry Yellow 4.5 mg (hypromellose 2.813 mg, titanium dioxide (E171) 1.350 mg, macrogol 400 0.281 mg, iron oxide yellow colorant (E172) 0.056 mg). Description: 5 mg: Almond-shaped, pink, film-coated tablets, embossed with "TL" on one side and "5" on the other. 10 mg: Almond-shaped, pale yellow, film-coated tablets, embossed with "TL" on one side and "10" on the other. Pharmacotherapeutic group: Antidepressant. Pharmacological properties. Pharmacodynamics. Mechanism of action. The mechanism of action of vortioxetine appears to be related to its direct serotonergic activity and inhibition of the serotonin transporter. Preclinical studies show that vortioxetine acts as an antagonist at 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist at 5-HT1B receptors, and a full agonist at 5-HT1A receptors, as well as inhibiting the 5-HT transporter, thereby modulating serotonergic, and possibly noradrenergic, dopaminergic neurotransmission, as well as histamine, acetylcholine, GABA, and glutamate systems. This multimodal pharmacological activity appears to be the basis for vortioxetine's antidepressant and anxiolytic properties, while also contributing to improvements in cognitive function, learning, and memory, as observed in animal studies. However, as the individual contribution of each pharmacological target to the observed pharmacodynamic profile of vortioxetine is unclear, extrapolation of these preclinical data to humans should be done with caution. In two ongoing human studies using positron emission tomography to quantify the degree of 5-HT transporter occupancy at different doses of vortioxetine (using 11C-MADAM or 11C-DASB ligands), the following data were obtained: the mean occupancy of 5-HT transporters 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% at a dose of 20 mg/day. Clinical efficacy and safety. The efficacy and safety of vortioxetine have been studied in a series of clinical trials involving 6700 patients, of whom more than 3700 participated in short-term studies (≤12 weeks) for major depressive disorder. Twelve double-blind, placebo-controlled, 6/8-week fixed-dose studies were conducted to determine the short-term efficacy of vortioxetine in adult patients (including elderly patients) with major depressive disorder. Vortioxetine efficacy, in at least one dose group, was demonstrated in 9 out of 12 studies, where, compared to placebo, there was at least a 2-point change on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HAM-D24). This was clinically confirmed by the number of patients who responded to therapy and achieved remission, as well as improvement in the Clinical Global Impression-Improvement (CGI-I) scale. The efficacy of vortioxetine increased with dose escalation. Under short-term placebo-controlled study conditions in adults, the efficacy of individual studies was confirmed by a meta-analysis of the mean change in total MADRS score at 6-8 weeks. According to the meta-analysis of these studies, the difference compared to placebo was statistically significant: -2.3 points (p=0.007); -3.6 points (p<0.001); -4.6 points (p<0.001) for doses of 5, 10, and 20 mg/day, respectively. For a dose of 15 mg/day, a statistically significant difference compared to placebo was not achieved in the meta-analysis data, but the mean difference compared to placebo was -2.6 points. The efficacy of vortioxetine was also confirmed in a consolidated analysis, where the percentage of responders ranged from 46% to 49% with vortioxetine, compared to 34% with placebo (p<0.01; NRI analysis). Furthermore, vortioxetine in the dose range of 5-20 mg/day demonstrated efficacy across a broad spectrum of depressive symptoms (assessed by changes in MADRS scores on all individual subscales). The efficacy of vortioxetine at doses of 10 or 20 mg/day was also shown in a 12-week, double-blind, flexible-dose comparative study with agomelatine 25 or 50 mg/day in patients with major depressive disorder. Compared to agomelatine, vortioxetine demonstrated statistically significant superiority in total MADRS score, which was also clinically significant in terms of the number of patients who responded to treatment, achieved remission, and improved according to the CGI-I scale. Maintenance therapy. Persistence of antidepressant effect. The persistence of antidepressant effect during maintenance therapy was demonstrated in a relapse prevention study. Patients who were in remission after 12 weeks of open-label vortioxetine therapy were randomized to placebo and vortioxetine 5 or 10 mg/day groups. They were monitored for relapse during a double-blind study that lasted at least 24 weeks (24 to 64 weeks). Vortioxetine showed superiority over placebo (p=0.004) in terms of time to relapse of major depressive disorder, the primary endpoint, with a hazard ratio of 2.0; this means that the risk of relapse was twice as high in the placebo group compared to the vortioxetine group. Elderly patients. In an 8-week, double-blind, placebo-controlled study in elderly patients with depression (≥65 years, n=452, of whom 156 received vortioxetine treatment) at fixed doses, vortioxetine 5 mg/day showed superiority over placebo in terms of improvement on the MADRS and HAM-D24 scales. The difference between vortioxetine and placebo was 4.7 points on the MADRS scale at week 8 of therapy (MMRM analysis). Patients with severe depression or depression with prominent anxiety symptoms. The efficacy of vortioxetine was also demonstrated in patients with severe depression (initial total MADRS score ≥30) and patients with depression and prominent anxiety symptoms (initial total HAM-A score ≥20) in a short-term study in adults (mean difference from placebo on MADRS scale at weeks 6 and 8 ranged from 2.8 to 7.3 points and 3.6 to 7.3 points, respectively (MMRM analysis)). In a separate study in the elderly, vortioxetine also showed efficacy in this patient group. The persistence of antidepressant effect in this category of patients was also demonstrated in a long-term relapse prevention study. Effect of vortioxetine on the Digit Symbol Substitution Test (DSST), assessment of quality of life basic activities (UPSA), and scores on the Perceived Deficits Questionnaire (PDQ) and Cognitive and Physical Functioning Questionnaire (CPFQ) (subjective measures). The efficacy of vortioxetine (5-20 mg/day) in patients with major depressive disorder was studied in two short-term placebo-controlled studies in adults and one in elderly patients. Vortioxetine showed a statistically significant effect on the DSST score compared to placebo (Δ = 1.75 (p=0.019) to 4.26 (p<0.0001)) in two studies in adolescents and Δ = 2.79 (p=0.023) in a study of elderly patients. In a meta-analysis of the mean change in the number of correct symbols in the DSST from baseline (ANCOVA, LOCF) across these three studies, vortioxetine differed from placebo (p<0.05) with a standardized effect size of 0.35. When adjusted for changes 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 size of 0.24. One study assessed the effect of vortioxetine on functional abilities using the University of California San Diego Performance-based Skills Assessment (UPSA). Vortioxetine was statistically different from placebo with a score of 8.0 for vortioxetine compared to 5.1 for placebo (p=0.0003). In one study, vortioxetine outperformed placebo in terms of subjective measures as assessed by the Perceived Deficits Questionnaire, with a score of -14.6 for vortioxetine and -10.5 for placebo (p=0.002). Vortioxetine did not differ from placebo in terms of subjective measures as assessed by the Cognitive and Physical Functioning Questionnaire, with a score of -8.1 for vortioxetine and -6.9 for placebo (p=0.086). Tolerability and safety. The tolerability and safety of vortioxetine were established during short-term and long-term studies in the dose range of 5 to 20 mg/day. Information on adverse side effects is provided in the "Side Effects" section. Compared to placebo, vortioxetine did not increase the incidence of insomnia or somnolence. The potential for withdrawal symptoms after abrupt discontinuation of vortioxetine treatment was assessed sequentially in short-term and long-term placebo-controlled clinical trials. No clinically significant difference was observed compared to placebo in the severity or incidence of withdrawal symptoms after short-term (6-12 weeks) or long-term (24-64 weeks) vortioxetine therapy. The incidence of spontaneous complaints of sexual side effects was low and similar to placebo during both short-term and long-term studies with vortioxetine. In studies using the Arizona Sexual Experience Scale (ASEX), the incidence of treatment-emergent sexual dysfunction (TESD) and the total ASEX score did not differ significantly from placebo at vortioxetine doses of 5-15 mg/day. At a vortioxetine dose of 20 mg/day, an increased incidence of sexual dysfunction was observed compared to placebo (difference in incidence 14.2%, 95% confidence interval (1.4; 27.0)). The effect of vortioxetine on sexual function was further assessed in an 8-week, double-blind comparative study using flexible dosing (n=424) compared to escitalopram in patients treated with SSRIs (citalopram, paroxetine, or sertraline) for at least 6 weeks, with a low level of depressive symptoms ("Clinical Global Impression-Severity of Illness" score at baseline ≤ 3) and SSRI-induced TESD from prior treatment. Compared to escitalopram 10-20 mg/day, vortioxetine 10-20 mg/day showed statistically significantly less TESD, as measured by the change in the total score of the Change in Sexual Function Questionnaire-14 (CSFQ-14) at week 8 (2.2 points, p=0.013). The proportion of patients who responded to treatment at week 8 did not differ significantly between the vortioxetine group (162 (74.7%)) and the escitalopram group (137 (66.2%)) (OR 1.5 (p=0.057)). Antidepressant effect was observed in both treatment groups. During short-term and long-term studies, vortioxetine, compared to placebo, did not affect body weight, heart rate, or blood pressure. Vortioxetine did not show clinically significant effects on renal and hepatic function parameters in clinical studies. In patients with major depressive disorder, vortioxetine did not show clinically significant effects on ECG parameters, including QT, QTc, PR, and QRS intervals. In a study of the QTc interval in healthy subjects, vortioxetine up to 40 mg/day did not affect its duration. Children and adolescents (under 18 years). One randomized, double-blind, placebo-controlled, 8-week fixed-dose study was conducted in patients aged 12 to 17 years with major depressive disorder, comparing vortioxetine with an active comparator. The study included a 4-week, single-blind run-in period with placebo and standardized psychosocial intervention (N=777). Only patients who did not respond during the run-in period were randomized (N=615). Based on the total score of the Children's Depression Rating Scale-Revised (CDRS-R), vortioxetine 10 and 20 mg/day was not statistically more effective than placebo. The active comparator (fluoxetine, 20 mg/day) differed statistically from placebo in terms of total CDRS-R score. Overall, the adverse event profile of vortioxetine in adolescents was similar to that in adults, with the exception of more frequent events related to abdominal pain and suicidal ideation in adolescents compared to adults. The incidence of drug discontinuation due to adverse events (mainly suicidal ideation, nausea, and vomiting) was highest in patients receiving vortioxetine 20 mg/day (5.6%), compared to vortioxetine 10 mg/day (2.7%), fluoxetine (3.3%), and placebo (1.3%). The most frequent adverse events during vortioxetine use were nausea, vomiting, and headache. Suicidal ideation and behavior occurred as adverse events during both the 4-week single-blind run-in period (placebo 13/777 [1.7%]) and the 8-week treatment period (vortioxetine 10 mg/day 2/147 [1.4%], vortioxetine 20 mg/day 6/161 [3.7%], fluoxetine 6/153 [3.9%], placebo 0/154 [0%]). The incidence of suicidal ideation and behavior, measured by the Columbia-Suicide Severity Rating Scale (C-SSRS), was similar across all patient groups. Pharmacokinetics. Absorption. Vortioxetine is slowly but well absorbed after oral administration. Peak plasma concentrations are reached 7-11 hours after administration. After multiple doses of 5, 10, or 20 mg/day, the mean peak plasma concentration (Cmax) is 9-33 ng/mL. Absolute bioavailability is 75%. Food intake does not affect the pharmacokinetics of the drug (see "Dosage and Administration"). Distribution. The mean volume of distribution (Vss) is 2600 L, indicating extensive extravascular distribution. Plasma protein binding is high (98-99%) and appears to be concentration-independent. Biotransformation. Vortioxetine is extensively metabolized in the liver, primarily by oxidation mediated by the CYP2D6 isoenzyme and, to a lesser extent, by CYP3A4/5 and CYP2C9 isoenzymes, followed by glucuronidation. In drug interaction studies, vortioxetine did not show inhibitory or inductive effects on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 isoenzymes (see "Interactions with other medicinal products and other forms of interaction"). Vortioxetine is a weak substrate and inhibitor of P-glycoprotein. The main metabolite of vortioxetine is pharmacologically inactive. Elimination. The mean terminal elimination half-life and oral clearance are 66 hours and 33 L/h, respectively. Approximately 2/3 of the inactive metabolite of vortioxetine is excreted in urine and approximately 1/3 in feces. A small amount of vortioxetine is excreted unchanged in feces. Steady-state plasma concentrations are reached in approximately 2 weeks. Linearity/non-linearity. The pharmacokinetics are linear and time-independent within the studied dose range (2.5-60 mg/day). Based on the AUC0-24h and the terminal elimination half-life, the accumulation index after multiple doses of 5-20 mg/day is 5-6. Special populations. Elderly patients. In elderly healthy subjects (≥65 years; n=20), vortioxetine exposure increased by 27% (Cmax and AUC) compared to a control group of younger healthy subjects (≤45 years) after multiple doses of 10 mg/day. The minimum effective dose of vortioxetine, 5 mg/day, should always be used as the starting dose in patients ≥65 years of age (see "Dosage and Administration"). Doses of vortioxetine greater than 10 mg/day in elderly patients should be administered with caution (see "Special Precautions"). Renal impairment. Compared to a control group of healthy subjects, renal impairment, assessed by the Cockcroft-Gault formula (mild, moderate, or severe; n=8 per group), after a single dose of 10 mg/day of vortioxetine, caused a moderate increase (up to 30%) in vortioxetine exposure. In patients with end-stage renal disease, dialysis caused only a minor reduction in exposure (AUC and Cmax decreased by 13% and 27%, respectively, n=8) after a single 10 mg dose of vortioxetine. Dose adjustment is not required regardless of renal function (see "Dosage and Administration" and "Special Precautions"). Hepatic impairment. The pharmacokinetics of the drug in patients (N=6-8) with mild, moderate, or severe hepatic impairment (Child-Pugh criteria A, B, and C, respectively) were comparable to those in healthy volunteers. AUC change was less than 10% in patients with mild or moderate hepatic impairment and more than 10% in patients with severe hepatic impairment. Cmax change was less than 25% in all groups. Dose adjustment is not required according to hepatic function (see "Dosage and Administration" and "Special Precautions"). CYP2D6 isoenzyme genotype. Vortioxetine plasma concentrations were approximately twice as high in patients with reduced metabolic activity of the CYP2D6 isoenzyme compared to extensive metabolizers. Concomitant use of strong inhibitors of CYP3A4/2C9 isoenzymes in patients with reduced metabolic activity of the CYP2D6 isoenzyme may potentially lead to increased vortioxetine exposure (see "Interactions with other medicinal products and other forms of interaction"). In patients with very rapid metabolism of the CYP2D6 isoenzyme, vortioxetine plasma concentration at 10 mg/day was within the range observed in extensive metabolizers at doses of 5 mg/day and 10 mg/day. Dose adjustment may be considered based on individual patient response (see "Dosage and Administration"). Children and adolescents (under 18 years). The pharmacokinetics of vortioxetine in children and adolescents with major depressive disorder, after single oral administration of 5-20 mg/day, were characterized using population modeling based on data from pharmacokinetic (7-17 years) and efficacy and safety (12-17 years) studies. The pharmacokinetics of vortioxetine in children and adolescents were similar to those in adult patients. Preclinical safety data. In studies of general toxicity in mice, rats, and dogs, vortioxetine administration was mainly associated with CNS effects, including salivation (rats and dogs), pupillary dilation (dogs), and two episodes of seizures in dogs. At the maximum recommended therapeutic dose of 20 mg/day, no convulsive activity was observed, considering a safety margin of 5%. Organic toxicity was limited to the kidneys (rats) and liver (mice and rats). Kidney changes in rats (glomerulonephritis, tubular obstruction, crystals in renal tubules) and liver changes in mice (hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, crystals in bile ducts) were observed at exposures 2 times (rats) and 10 times (mice) the maximum recommended human dose of 20 mg/day. These events were mainly associated with crystal obstruction of renal tubules and bile ducts, characteristic of rodents, and are considered less likely to occur in humans. Vortioxetine did not show genotoxic effects in standard in vitro and in vivo tests. Based on standard 2-year carcinogenicity studies in mice or rats, vortioxetine does not pose a carcinogenic risk to humans. Vortioxetine did not affect fertility, mating ability, reproductive organ function or morphology, or sperm motility in rats. Vortioxetine did not show teratogenic effects in rats or rabbits, although effects on fetal weight and delayed ossification were observed in rats at vortioxetine exposures 10 times the maximum daily dose of 20 mg/day used in humans. Similar effects were observed in rabbits at subtherapeutic exposures. In pre- and postnatal studies in rats, vortioxetine administration at doses that did not cause maternal toxicity and were equivalent to the human dose of 20 mg/day was associated with increased offspring mortality, reduced body weight gain rate, and delayed development (see "Use in pregnancy and lactation"). Vortioxetine was excreted in the milk of lactating rats (see "Use in pregnancy and lactation"). In juvenile toxicity studies in rats, data obtained with vortioxetine therapy were similar to those obtained in adult animals. Environmental risk assessment studies showed that vortioxetine has the potential for persistence, bioaccumulation, and ecotoxicity (risk to fish). However, at the doses recommended for patients, vortioxetine poses a negligible risk to the aquatic and terrestrial environment. Indication for use. BRINTELLIX is indicated for the treatment of major depressive episodes in adults. Contraindications. Hypersensitivity to the active substance or any of the excipients. Concomitant use of non-selective monoamine oxidase inhibitors or selective MAO-A inhibitors (see "Interactions with other medicinal products and other forms of interaction"). Children and adolescents under 18 years of age (safety and efficacy not established). Precautions. Severe renal and hepatic impairment; mania and hypomania; pharmacologically uncontrolled epilepsy, history of seizures; pronounced suicidal behavior; liver cirrhosis; predisposition to bleeding; concomitant use with MAO-B inhibitors (selegiline, rasagiline); serotonergic drugs; drugs that lower the seizure threshold; lithium, tryptophan; St. John's Wort-containing preparations; oral anticoagulants and drugs affecting platelet function; drugs that can cause hyponatremia; electroconvulsive therapy; elderly age. Use in pregnancy and lactation. Pregnancy. Data on the use of vortioxetine in pregnant women are limited. Animal studies have not shown toxic effects on reproductive function (see "Pharmacological Properties"). In neonates whose mothers received serotonergic drugs in late pregnancy, the following symptoms may occur: respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, increased neuro-reflex excitability, irritability, lethargic sleep, persistent crying, somnolence, and poor sleep. These symptoms may be related to both withdrawal syndrome and excessive serotonergic activity. In most cases, such complications begin at birth or later (<24 hours). According to available epidemiological study data, the use of selective serotonin reuptake inhibitors during pregnancy, especially in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although the association of this condition with vortioxetine use has not been studied, given the mechanism of action (increase in serotonin concentration), the potential risk cannot be excluded. Use of BRINTELLIX during pregnancy should only be considered when the expected benefit to the mother outweighs the potential risk to the fetus. Based on reported clinical cases, the risk of postpartum hemorrhage is likely to increase (2-fold) after the use of selective serotonin and norepinephrine reuptake inhibitors in the month preceding delivery. Although no study has investigated the link between postpartum hemorrhage and vortioxetine treatment, there is a potential risk of this event given the relevant mechanism of action (see "Special Precautions"). Breastfeeding. Available preclinical pharmacokinetic and toxicological studies have shown that vortioxetine and its metabolites are excreted in breast milk. Vortioxetine may also be excreted in human breast milk (see "Pharmacological Properties"). The risk to the infant during breastfeeding cannot be excluded. The decision to discontinue breastfeeding or vortioxetine therapy should be made considering the balance of benefits of breastfeeding for the infant and therapy for the mother. Fertility. Fertility studies in female and male rats have shown that vortioxetine does not affect fertility, sperm quality, or mating ability (see "Pharmacological Properties"). In humans, cases of antidepressant use (SSRIs) have shown effects on sperm quality that are reversible. Effects on human fertility have not been observed to date. Dosage and administration. Dosage regimen. The initial and recommended dose of BRINTELLIX in adult patients under 65 years of age is 10 mg once daily. The daily dose may be increased to a maximum dose of 20 mg vortioxetine once daily or decreased to a minimum dose of 5 mg vortioxetine once daily, depending on the individual patient's response. Once depressive symptoms have completely resolved, treatment should be continued for at least 6 months to consolidate the antidepressant effect. Discontinuation of treatment. Patients taking vortioxetine can discontinue the drug abruptly without the need for gradual dose reduction (see "Pharmacological Properties"). Special populations. Elderly patients (≥65 years). In patients ≥65 years of age, the minimum effective dose of BRINTELLIX, 5 mg once daily, should always be used as the starting dose. Caution is required when treating patients ≥65 years with vortioxetine doses greater than 10 mg once daily, as data on the use of the drug in this patient group are limited (see "Special Precautions"). Cytochrome P450 inhibitors. Depending on the individual patient's response, it may be necessary to reduce the dose of BRINTELLIX when adding therapy with strong CYP2D6 isoenzyme inhibitors (e.g., bupropion, quinidine, fluoxetine, paroxetine) (see "Interactions with other medicinal products and other forms of interaction"). Cytochrome P450 inducers. Depending on the individual patient's response, it may be necessary to adjust the dose of BRINTELLIX when adding therapy with a broad spectrum of cytochrome P450 inducers (e.g., rifampicin, carbamazepine, phenytoin) (see "Interactions with other medicinal products and other forms of interaction"). Children and adolescents (under 18 years). The safety and efficacy of BRINTELLIX in children aged 7 to 11 years have not been established. Data are not available for this patient group (see "Special Precautions"). BRINTELLIX should not be used in adolescents aged 12 to 17 years with major depressive disorder, as its efficacy has not been demonstrated in this age group. The safety of BRINTELLIX in adolescents aged 12 to 17 years is described in the "Special Precautions" and "Side Effects" sections. Renal or hepatic impairment. Dose adjustment is not required according to renal or hepatic function (see "Special Precautions" and "Pharmacological Properties"). Method of administration. BRINTELLIX is intended for oral use. Film-coated tablets can be taken independently of meals. Side effects. Characterization of the safety profile. The most frequent adverse reaction was nausea. The list of adverse reactions is provided in the table below. Adverse reactions are classified by frequency as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); frequency unknown (frequency cannot be estimated from available data). The listed list is based on clinical trial data and post-marketing experience. Organ system class Frequency Adverse reactions Immune system disorders Unknown* Anaphylactic reaction Endocrine disorders Unknown* Hyperprolactinemia Metabolism and nutrition disorders Unknown* Hyponatremia Psychiatric disorders Common Unusual dreams Unknown* Insomnia Unknown* Agitation, aggression Nervous system disorders Common Dizziness Unknown* Serotonin syndrome Headache Visual disorders Rare Mydriasis, which may lead to acute angle-closure glaucoma Vascular disorders Uncommon Hot flush Unknown* Bruising (including ecchymosis, purpura, epistaxis, gastrointestinal bleeding, vaginal bleeding) Gastrointestinal disorders Very common Nausea Common Diarrhea, constipation, vomiting Skin and subcutaneous tissue disorders Common Pruritus, including generalized pruritus Hyperhidrosis Uncommon Night sweats Unknown* Angioedema, urticaria, rash *Based on post-marketing experience. Description of individual adverse reactions. Nausea. Nausea was generally mild to moderate in severity and occurred within the first 2 weeks of treatment. Reactions were mostly transient and did not lead to discontinuation of treatment. Gastrointestinal adverse reactions such as nausea were more frequent in women than in men. Elderly patients. For vortioxetine doses of 10 mg or more once daily, the discontinuation rate was higher in patients ≥65 years of age. At vortioxetine doses of 20 mg once daily, the incidence of nausea and constipation was higher in patients ≥65 years (42% and 15%, respectively) compared to patients <65 years (27% and 4%, respectively) (see "Special Precautions"). Sexual dysfunction. In clinical studies, sexual dysfunction was assessed using the Arizona Sexual Experience Scale (ASEX). Doses of 5 to 15 mg did not show data different from placebo. However, vortioxetine 20 mg was associated with an increased incidence of sexual dysfunction (TESD) (see "Pharmacological Properties"). Class-specific effect. Epidemiological studies, mainly involving patients aged 50 and over, have shown an increased risk of bone fractures in patients taking drugs of the corresponding pharmacological class of antidepressants (SSRIs and tricyclic antidepressants). The mechanism causing this risk is unknown, as is whether this risk is associated with vortioxetine intake. Children and adolescents (under 18 years). In total, 308 patients aged 12 to 17 years with major depressive disorder participated in double-blind, placebo-controlled studies of vortioxetine treatment. Overall, the adverse event profile of vortioxetine was similar to that in adults, with the exception of more frequent occurrences of abdominal pain and suicidal ideation in adolescents compared to adults. Overdose. Symptoms. In clinical studies, oral administration of vortioxetine in doses ranging from 40 mg to 75 mg led to an exacerbation of the following adverse reactions: nausea, postural dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and hot flush. Post-marketing experience mainly includes information on vortioxetine overdose up to 80 mg. In most cases, symptoms were absent or mild. The most frequently reported symptoms were nausea and vomiting. Information on overdose with vortioxetine doses exceeding 80 mg is limited. Seizures and serotonin syndrome have been reported after doses several times higher than the therapeutic range. Treatment. In case of overdose, the patient should be monitored and symptomatic treatment provided. Further medical observation in specialized facilities is also recommended. Interactions with other medicinal products and other forms of interaction. Vortioxetine is extensively metabolized in the liver, primarily by oxidation catalyzed by the CYP2D6 isoenzyme and, to a lesser extent, by CYP3A4/5 and CYP2C9 isoenzymes (see "Pharmacological Properties"). Possible effects of other drugs on the pharmacological action of vortioxetine. Irreversible non-selective MAO inhibitors. Due to the risk of serotonin syndrome, concomitant use of vortioxetine with irreversible non-selective MAO inhibitors is contraindicated. Vortioxetine may be initiated at least 14 days after discontinuation of irreversible non-selective MAO inhibitors. Discontinuation of vortioxetine should occur at least 14 days before starting irreversible non-selective MAO inhibitors (see "Contraindications"). Reversible selective MAO-A inhibitors (moclobemide). Concomitant use of vortioxetine and reversible selective MAO-A inhibitors, such as moclobemide, is contraindicated (see "Contraindications"). If concomitant use is deemed necessary, the concomitant drug should be initiated at the minimum dose. Treatment should be conducted under clinical observation for signs of serotonin syndrome (see "Special Precautions"). Reversible non-selective MAO inhibitors (linezolid). Concomitant use of vortioxetine and reversible non-selective MAO inhibitors, such as the antibiotic linezolid, is contraindicated (see "Contraindications"). If concomitant use is deemed necessary, the concomitant drug should be initiated at the minimum dose. Treatment should be conducted under clinical observation for signs of serotonin syndrome (see "Special Precautions"). Irreversible selective MAO-B inhibitors (selegiline, rasagiline). Although the risk of serotonin syndrome is lower with concomitant use of vortioxetine and selective MAO-B inhibitors than with selective MAO-A inhibitors, combined use of vortioxetine and irreversible MAO-B inhibitors, such as selegiline or rasagiline, should be done with caution. If used concomitantly, the patient should be under clinical observation for signs of serotonin syndrome (see "Special Precautions"). Serotonergic drugs. Concomitant use of vortioxetine with other drugs with serotonergic effects, such as opioids (including tramadol) and triptans (including sumatriptan), may lead to serotonin syndrome (see "Special Precautions"). St. John's Wort. Concomitant use of antidepressants and St. John's Wort-containing (Hypericum perforatum) preparations with serotonergic effects may increase the incidence of adverse reactions, including serotonin syndrome (see "Special Precautions"). Drugs that lower the seizure threshold. Antidepressants with serotonergic effects may lower the seizure threshold. Concomitant use with drugs that lower the seizure threshold (e.g., antidepressants (tricyclic antidepressants, selective serotonin and norepinephrine reuptake inhibitors), neuroleptics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion, tramadol) should be done with caution (see "Special Precautions"). ECT (Electroconvulsive Therapy). There is currently no clinical experience with the concomitant use of vortioxetine and ECT, so caution is advised with such use. CYP2D6 isoenzyme inhibitors. In a study of vortioxetine 10 mg/day with bupropion (a strong CYP2D6 isoenzyme inhibitor) at a dose of 150 mg twice daily for 14 days in healthy subjects, vortioxetine exposure (AUC) increased 2.3-fold. Adverse events were more frequent when bupropion was added to ongoing vortioxetine therapy than when vortioxetine was added to ongoing bupropion therapy. Depending on the individual patient's response, dose reduction of vortioxetine should be considered when adding a strong CYP2D6 isoenzyme inhibitor (e.g., bupropion, quinidine, fluoxetine, paroxetine) to ongoing vortioxetine therapy (see "Special Precautions"). CYP3A4, CYP2C9, and CYP2C19 isoenzyme inhibitors. After 6 days of ketoconazole (CYP3A4/5 isoenzyme and P-glycoprotein inhibitor) 400 mg/day or fluconazole (CYP2C9, CYP2C19, and CYP3A4/5 isoenzyme inhibitor) 200 mg/day, vortioxetine exposure (AUC) increased 1.3-fold and 1.5-fold, respectively, when vortioxetine was added in healthy subjects. Dose adjustment is not required. A single dose of omeprazole 40 mg (CYP2C19 isoenzyme inhibitor) did not show inhibitory effects on the pharmacokinetics of multiple doses of vortioxetine in healthy subjects. Interaction in patients with weak CYP2D6 isoenzyme activity. Specific studies of concomitant use of strong CYP3A4 isoenzyme inhibitors (e.g., itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, conivaptan, and many HIV protease inhibitors) and CYP2C9 isoenzyme inhibitors (e.g., fluconazole and amiodarone) in patients with reduced CYP2D6 isoenzyme activity (see "Pharmacological Properties") have not been conducted. However, it is expected that such use in these patients will lead to more pronounced vortioxetine exposure compared to the moderate effects described above. Depending on the individual patient's response, a lower dose of vortioxetine may be necessary with concomitant use of strong CYP3A4 or CYP2C9 isoenzyme inhibitors or in individuals with slow CYP2D6 metabolism. P450 cytochrome inducers. After 10 days of rifampicin (broad-spectrum CYP isoenzyme inducer) 600 mg/day, vortioxetine exposure (AUC) decreased by 72% after a single 20 mg dose of vortioxetine in healthy subjects. Depending on the individual patient's response, dose adjustment of vortioxetine should be considered when adding a strong broad-spectrum P450 cytochrome inducer (e.g., rifampicin, carbamazepine, phenytoin) to ongoing vortioxetine therapy (see "Dosage and Administration"). Alcohol. Concomitant use of single doses of vortioxetine (20 mg and 40 mg) and ethanol (0.6 g/kg) in healthy subjects did not result in significant pharmacokinetic changes of vortioxetine or ethanol, or significant impairment of cognitive functions compared to placebo. However, alcohol consumption is not recommended during antidepressant therapy. Acetylsalicylic acid. A single dose of acetylsalicylic acid 150 mg/day did not alter the pharmacokinetics of multiple doses of vortioxetine in healthy subjects. Possible effects of vortioxetine on the pharmacological action of other drugs. Anticoagulants and antiplatelet agents. Compared to placebo, vortioxetine did not show significant effects on prothrombin parameters, international normalized ratio (INR), or R-/S-warfarin ratio in plasma during concomitant use of multiple doses of vortioxetine and fixed doses of warfarin in healthy subjects. Similarly, compared to placebo, vortioxetine did not show significant inhibitory effects on platelet aggregation or on the pharmacokinetics of acetylsalicylic acid and salicylic acid after multiple doses of vortioxetine with concomitant use of acetylsalicylic acid 150 mg/day in healthy subjects. Nevertheless, caution should be exercised with concomitant use of vortioxetine and oral anticoagulants or antiplatelet agents due to the potential risk of bleeding due to pharmacodynamic interactions (see "Special Precautions"). P450 cytochrome substrates. In vitro studies have not shown vortioxetine's ability to inhibit or induce P450 cytochrome system isoenzymes (see "Pharmacological Properties"). After multiple doses of vortioxetine in healthy subjects, no inhibitory effects on the activity of P450 cytochrome system isoenzymes CYP2C19 (omeprazole, diazepam), CYP3A4/5 (ethinylestradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (tolbutamide, S-warfarin), CYP1A2 (caffeine), or CYP2D6 (dextromethorphan) were observed. No pharmacodynamic interactions were observed either. No significant impairment of cognitive function was observed compared to placebo during combined use of vortioxetine and a single dose of diazepam 10 mg. Compared to placebo, no significant effect of vortioxetine on sex hormone levels was observed during concomitant use with oral combined contraceptives (ethinylestradiol 30 mcg + levonorgestrel 150 mcg). Lithium, tryptophan. No clinically significant changes were observed in healthy subjects during concomitant use of multiple doses of lithium and vortioxetine. However, given that cases of potentiation of serotonergic antidepressant effects have been described with concomitant use of lithium or tryptophan, combined use of vortioxetine with these drugs should be done with caution. Effect on urine screening results for drug detection. Cases of false-positive urine immunoassay results for methadone have been reported in patients taking vortioxetine. Urine screening results for drugs should be interpreted with caution, and alternative analytical methods (e.g., chromatographic methods) should be considered to confirm the results. Special precautions. Use in children and adolescents under 18 years of age. The use of BRINTELLIX is not recommended for the treatment of depression in children aged 7 to 11 years, as the safety and efficacy of vortioxetine have not been established in this age group (see "Dosage and Administration"). BRINTELLIX should not be used in adolescents aged 12 to 17 years with major depressive disorder, as its efficacy has not been demonstrated (see "Pharmacodynamics"). In general, the adverse event profile of vortioxetine in adolescents was similar to that in adult patients, with the exception of more frequent occurrences of abdominal pain and suicidal ideation in adolescents compared to adults (see "Pharmacodynamics" and "Side Effects"). In clinical trials in children and adolescents receiving antidepressants, suicidal behavior (suicidal attempts and suicidal ideation) and hostility (predominantly aggressive behavior, tendency to opposition and irritability) were more frequent compared to the placebo group. Suicide/suicidal ideation or clinical worsening of depression is associated with an increased risk of suicidal ideation, self-harm, and suicide (suicidal behavior). This risk persists until significant remission is achieved. Since improvement may not be observed for the first few weeks of therapy or even longer, patients should be under continuous observation until their condition improves. General clinical practice shows that the risk of suicide may increase in the early stages of recovery. Patients with a history of suicidal behavior or patients with significant suicidal ideation are at higher risk of suicidal ideation or suicide attempts, so they require close monitoring during treatment. In adult patients with mental disorders, a meta-analysis of placebo-controlled clinical trials showed an increased risk of suicidal behavior in patients under 25 years of age compared to placebo when using antidepressants. Patients require close monitoring, especially those at high risk of suicide, particularly at the beginning of treatment or when the drug dose is changed. Patients (and their caregivers) should be warned to pay attention to any signs of clinical worsening, development of suicidal behavior and suicidal ideation, as well as unusual changes in behavior, and to seek immediate medical attention if such symptoms develop. Seizures. There is a risk of seizures when using antidepressants. Therefore, vortioxetine should be used with caution in patients with a history of seizures or in patients with unstable epilepsy (see "Interactions with other medicinal products"). If seizures occur or their frequency increases, vortioxetine treatment should be discontinued. Serotonin syndrome or neuroleptic malignant syndrome. Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS) are potentially life-threatening conditions that can develop with vortioxetine use. The risk of developing SS and NMS increases with concomitant use of serotonergic drugs (including opioids and triptans), drugs affecting serotonin metabolism (including SSRIs), antipsychotics, or other dopamine antagonists. Patients should be monitored for objective and subjective symptoms of SS or NMS (see "Contraindications" and "Interactions with other medicinal products and other forms of interaction"). Symptoms of serotonin syndrome include changes in mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). If such symptoms develop, vortioxetine therapy should be discontinued immediately and symptomatic treatment initiated. Mania/hypomania. Vortioxetine should be used with caution in patients with a history of manic/hypomanic episodes. The drug should be discontinued if a manic state develops. Aggression/agitation. Patients treated with antidepressants, including vortioxetine, may also experience feelings of aggression, anger, agitation, and irritability. The patient's condition and disease status should be monitored. Patients (and their caregivers) should be warned to consult a doctor if aggressive behavior or agitation develops or if the condition worsens. Bleeding. Rare cases of hemorrhagic disorders, such as ecchymosis, purpura, gastrointestinal, and gynecological bleeding, have been reported with the use of serotonergic antidepressants, including vortioxetine. Selective serotonin and norepinephrine reuptake inhibitors, including vortioxetine, may also increase the risk of postpartum hemorrhage (see "Use in pregnancy and lactation"). The drug is recommended for use with caution in patients taking anticoagulants and/or drugs affecting platelet function (e.g., atypical antipsychotics, phenothiazines, most tricyclic antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs), and acetylsalicylic acid), as well as in patients with a known predisposition to bleeding/coagulation disorders (see "Interactions with other medicinal products and other forms of interaction"). Hyponatremia. Rare cases of hyponatremia have been reported with the use of serotonergic antidepressants (selective serotonin and norepinephrine reuptuptake inhibitors), possibly due to the syndrome of inappropriate secretion of antidiuretic hormone. Caution should be exercised when using vortioxetine in high-risk groups, such as elderly patients, patients with liver cirrhosis, or patients taking concomitant medications that may cause hyponatremia. If possible, vortioxetine should be discontinued in patients with symptomatic hyponatremia, and appropriate medical intervention should be initiated to correct their condition. Glaucoma. Cases of pupillary dilation have been reported with antidepressant use, including vortioxetine. This effect can lead to a reduction in the angle of vision, followed by an increase in intraocular pressure and the development of angle-closure glaucoma. Vortioxetine should be used with caution in patients with elevated intraocular pressure and those at risk of developing acute angle-closure glaucoma. Elderly patients. Data on the use of BRINTELLIX in elderly patients with major depressive episodes are limited. Therefore, caution should be exercised when treating patients ≥65 years with vortioxetine doses greater than 10 mg once daily (see "Dosage and Administration", "Pharmacological Properties", and "Side Effects"). Renal or hepatic impairment. Given that patients with renal or hepatic impairment are at risk, and considering that data on the use of BRINTELLIX in this subgroup are limited, caution should be exercised when treating such patients (see "Dosage and Administration" and "Pharmacological Properties"). BRINTELLIX contains sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, meaning it is essentially "sodium-free". Effects on ability to drive and use machines. BRINTELLIX has no or negligible influence on the ability to drive and use machines. However, since adverse reactions such as dizziness have been reported, patients should exercise caution when driving or operating machinery, especially at the beginning of vortioxetine treatment or when changing its dose. Dosage form. Film-coated tablets 5 mg, 10 mg, 15 mg, and 20 mg. 14 tablets in PVC/PVDC and aluminum foil blister packs. 1 or 2 blisters with instructions for use in a cardboard box with a tamper-evident closure mechanism with a perforated tear strip for initial opening control. Storage conditions. Not exceeding 25°C. Keep out of reach of children. Shelf life: 4 years. Do not use after the expiry date indicated on the packaging. Dispensing conditions: Pharmaceutical product group - II, dispensed by prescription form No. 3.

Active

vortioxetine

What is it?

BRINTELLIX Trade name: BRINTELLIX International Nonproprietary Name: Vortioxetine. Dosage form: Film-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, hypromellose 4.5 mg/4.5 mg/4.5 mg/4.5 mg, sodium starch glycolate (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 / 1.5 mg. Film coating: For 5 mg tablets - Opadry Pink 4.5 mg (hypromellose 2.813 mg, titanium dioxide (E171) 1.375 mg, macrogol 400 0.281 mg, iron oxide red colorant (E172) 0.032 mg); For 10 mg tablets - Opadry Yellow 4.5 mg (hypromellose 2.813 mg, titanium dioxide (E171) 1.350 mg, macrogol 400 0.281 mg, iron oxide yellow colorant (E172) 0.056 mg). Description: 5 mg: Almond-shaped, pink, film-coated tablets, embossed with "TL" on one side and "5" on the other. 10 mg: Almond-shaped, pale yellow, film-coated tablets, embossed with "TL" on one side and "10" on the other. Pharmacotherapeutic group: Antidepressant. Pharmacological properties. Pharmacodynamics. Mechanism of action. The mechanism of action of vortioxetine appears to be related to its direct serotonergic activity and inhibition of the serotonin transporter. Preclinical studies show that vortioxetine acts as an antagonist at 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist at 5-HT1B receptors, and a full agonist at 5-HT1A receptors, as well as inhibiting the 5-HT transporter, thereby modulating serotonergic, and possibly noradrenergic, dopaminergic neurotransmission, as well as histamine, acetylcholine, GABA, and glutamate systems. This multimodal pharmacological activity appears to be the basis for vortioxetine's antidepressant and anxiolytic properties, while also contributing to improvements in cognitive function, learning, and memory, as observed in animal studies. However, as the individual contribution of each pharmacological target to the observed pharmacodynamic profile of vortioxetine is unclear, extrapolation of these preclinical data to humans should be done with caution. In two ongoing human studies using positron emission tomography to quantify the degree of 5-HT transporter occupancy at different doses of vortioxetine (using 11C-MADAM or 11C-DASB ligands), the following data were obtained: the mean occupancy of 5-HT transporters 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% at a dose of 20 mg/day. Clinical efficacy and safety. The efficacy and safety of vortioxetine have been studied in a series of clinical trials involving 6700 patients, of whom more than 3700 participated in short-term studies (≤12 weeks) for major depressive disorder. Twelve double-blind, placebo-controlled, 6/8-week fixed-dose studies were conducted to determine the short-term efficacy of vortioxetine in adult patients (including elderly patients) with major depressive disorder. Vortioxetine efficacy, in at least one dose group, was demonstrated in 9 out of 12 studies, where, compared to placebo, there was at least a 2-point change on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating Scale (HAM-D24). This was clinically confirmed by the number of patients who responded to therapy and achieved remission, as well as improvement in the Clinical Global Impression-Improvement (CGI-I) scale. The efficacy of vortioxetine increased with dose escalation. Under short-term placebo-controlled study conditions in adults, the efficacy of individual studies was confirmed by a meta-analysis of the mean change in total MADRS score at 6-8 weeks. According to the meta-analysis of these studies, the difference compared to placebo was statistically significant: -2.3 points (p=0.007); -3.6 points (p<0.001); -4.6 points (p<0.001) for doses of 5, 10, and 20 mg/day, respectively. For a dose of 15 mg/day, a statistically significant difference compared to placebo was not achieved in the meta-analysis data, but the mean difference compared to placebo was -2.6 points. The efficacy of vortioxetine was also confirmed in a consolidated analysis, where the percentage of responders ranged from 46% to 49% with vortioxetine, compared to 34% with placebo (p<0.01; NRI analysis). Furthermore, vortioxetine in the dose range of 5-20 mg/day demonstrated efficacy across a broad spectrum of depressive symptoms (assessed by changes in MADRS scores on all individual subscales). The efficacy of vortioxetine at doses of 10 or 20 mg/day was also shown in a 12-week, double-blind, flexible-dose comparative study with agomelatine 25 or 50 mg/day in patients with major depressive disorder. Compared to agomelatine, vortioxetine demonstrated statistically significant superiority in total MADRS score, which was also clinically significant in terms of the number of patients who responded to treatment, achieved remission, and improved according to the CGI-I scale. Maintenance therapy. Persistence of antidepressant effect. The persistence of antidepressant effect during maintenance therapy was demonstrated in a relapse prevention study. Patients who were in remission after 12 weeks of open-label vortioxetine therapy were randomized to placebo and vortioxetine 5 or 10 mg/day groups. They were monitored for relapse during a double-blind study that lasted at least 24 weeks (24 to 64 weeks). Vortioxetine showed superiority over placebo (p=0.004) in terms of time to relapse of major depressive disorder, the primary endpoint, with a hazard ratio of 2.0; this means that the risk of relapse was twice as high in the placebo group compared to the vortioxetine group. Elderly patients. In an 8-week, double-blind, placebo-controlled study in elderly patients with depression (≥65 years, n=452, of whom 156 received vortioxetine treatment) at fixed doses, vortioxetine 5 mg/day showed superiority over placebo in terms of improvement on the MADRS and HAM-D24 scales. The difference between vortioxetine and placebo was 4.7 points on the MADRS scale at week 8 of therapy (MMRM analysis). Patients with severe depression or depression with prominent anxiety symptoms. The efficacy of vortioxetine was also demonstrated in patients with severe depression (initial total MADRS score ≥30) and patients with depression and prominent anxiety symptoms (initial total HAM-A score ≥20) in a short-term study in adults (mean difference from placebo on MADRS scale at weeks 6 and 8 ranged from 2.8 to 7.3 points and 3.6 to 7.3 points, respectively (MMRM analysis)). In a separate study in the elderly, vortioxetine also showed efficacy in this patient group. The persistence of antidepressant effect in this category of patients was also demonstrated in a long-term relapse prevention study. Effect of vortioxetine on the Digit Symbol Substitution Test (DSST), assessment of quality of life basic activities (UPSA), and scores on the Perceived Deficits Questionnaire (PDQ) and Cognitive and Physical Functioning Questionnaire (CPFQ) (subjective measures). The efficacy of vortioxetine (5-20 mg/day) in patients with major depressive disorder was studied in two short-term placebo-controlled studies in adults and one in elderly patients. Vortioxetine showed a statistically significant effect on the DSST score compared to placebo (Δ = 1.75 (p=0.019) to 4.26 (p<0.0001)) in two studies in adolescents and Δ = 2.79 (p=0.023) in a study of elderly patients. In a meta-analysis of the mean change in the number of correct symbols in the DSST from baseline (ANCOVA, LOCF) across these three studies, vortioxetine differed from placebo (p<0.05) with a standardized effect size of 0.35. When adjusted for changes 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 size of 0.24. One study assessed the effect of vortioxetine on functional abilities using the University of California San Diego Performance-based Skills Assessment (UPSA). Vortioxetine was statistically different from placebo with a score of 8.0 for vortioxetine compared to 5.1 for placebo (p=0.0003). In one study, vortioxetine outperformed placebo in terms of subjective measures as assessed by the Perceived Deficits Questionnaire, with a score of -14.6 for vortioxetine and -10.5 for placebo (p=0.002). Vortioxetine did not differ from placebo in terms of subjective measures as assessed by the Cognitive and Physical Functioning Questionnaire, with a score of -8.1 for vortioxetine and -6.9 for placebo (p=0.086). Tolerability and safety. The tolerability and safety of vortioxetine were established during short-term and long-term studies in the dose range of 5 to 20 mg/day. Information on adverse side effects is provided in the "Side Effects" section. Compared to placebo, vortioxetine did not increase the incidence of insomnia or somnolence. The potential for withdrawal symptoms after abrupt discontinuation of vortioxetine treatment was assessed sequentially in short-term and long-term placebo-controlled clinical trials. No clinically significant difference was observed compared to placebo in the severity or incidence of withdrawal symptoms after short-term (6-12 weeks) or long-term (24-64 weeks) vortioxetine therapy. The incidence of spontaneous complaints of sexual side effects was low and similar to placebo during both short-term and long-term studies with vortioxetine. In studies using the Arizona Sexual Experience Scale (ASEX), the incidence of treatment-emergent sexual dysfunction (TESD) and the total ASEX score did not differ significantly from placebo at vortioxetine doses of 5-15 mg/day. At a vortioxetine dose of 20 mg/day, an increased incidence of sexual dysfunction was observed compared to placebo (difference in incidence 14.2%, 95% confidence interval (1.4; 27.0)). The effect of vortioxetine on sexual function was further assessed in an 8-week, double-blind comparative study using flexible dosing (n=424) compared to escitalopram in patients treated with SSRIs (citalopram, paroxetine, or sertraline) for at least 6 weeks, with a low level of depressive symptoms ("Clinical Global Impression-Severity of Illness" score at baseline ≤ 3) and SSRI-induced TESD from prior treatment. Compared to escitalopram 10-20 mg/day, vortioxetine 10-20 mg/day showed statistically significantly less TESD, as measured by the change in the total score of the Change in Sexual Function Questionnaire-14 (CSFQ-14) at week 8 (2.2 points, p=0.013). The proportion of patients who responded to treatment at week 8 did not differ significantly between the vortioxetine group (162 (74.7%)) and the escitalopram group (137 (66.2%)) (OR 1.5 (p=0.057)). Antidepressant effect was observed in both treatment groups. During short-term and long-term studies, vortioxetine, compared to placebo, did not affect body weight, heart rate, or blood pressure. Vortioxetine did not show clinically significant effects on renal and hepatic function parameters in clinical studies. In patients with major depressive disorder, vortioxetine did not show clinically significant effects on ECG parameters, including QT, QTc, PR, and QRS intervals. In a study of the QTc interval in healthy subjects, vortioxetine up to 40 mg/day did not affect its duration. Children and adolescents (under 18 years). One randomized, double-blind, placebo-controlled, 8-week fixed-dose study was conducted in patients aged 12 to 17 years with major depressive disorder, comparing vortioxetine with an active comparator. The study included a 4-week, single-blind run-in period with placebo and standardized psychosocial intervention (N=777). Only patients who did not respond during the run-in period were randomized (N=615). Based on the total score of the Children's Depression Rating Scale-Revised (CDRS-R), vortioxetine 10 and 20 mg/day was not statistically more effective than placebo. The active comparator (fluoxetine, 20 mg/day) differed statistically from placebo in terms of total CDRS-R score. Overall, the adverse event profile of vortioxetine in adolescents was similar to that in adults, with the exception of more frequent events related to abdominal pain and suicidal ideation in adolescents compared to adults. The incidence of drug discontinuation due to adverse events (mainly suicidal ideation, nausea, and vomiting) was highest in patients receiving vortioxetine 20 mg/day (5.6%), compared to vortioxetine 10 mg/day (2.7%), fluoxetine (3.3%), and placebo (1.3%). The most frequent adverse events during vortioxetine use were nausea, vomiting, and headache. Suicidal ideation and behavior occurred as adverse events during both the 4-week single-blind run-in period (placebo 13/777 [1.7%]) and the 8-week treatment period (vortioxetine 10 mg/day 2/147 [1.4%], vortioxetine 20 mg/day 6/161 [3.7%], fluoxetine 6/153 [3.9%], placebo 0/154 [0%]). The incidence of suicidal ideation and behavior, measured by the Columbia-Suicide Severity Rating Scale (C-SSRS), was similar across all patient groups. Pharmacokinetics. Absorption. Vortioxetine is slowly but well absorbed after oral administration. Peak plasma concentrations are reached 7-11 hours after administration. After multiple doses of 5, 10, or 20 mg/day, the mean peak plasma concentration (Cmax) is 9-33 ng/mL. Absolute bioavailability is 75%. Food intake does not affect the pharmacokinetics of the drug (see "Dosage and Administration"). Distribution. The mean volume of distribution (Vss) is 2600 L, indicating extensive extravascular distribution. Plasma protein binding is high (98-99%) and appears to be concentration-independent. Biotransformation. Vortioxetine is extensively metabolized in the liver, primarily by oxidation mediated by the CYP2D6 isoenzyme and, to a lesser extent, by CYP3A4/5 and CYP2C9 isoenzymes, followed by glucuronidation. In drug interaction studies, vortioxetine did not show inhibitory or inductive effects on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 isoenzymes (see "Interactions with other medicinal products and other forms of interaction"). Vortioxetine is a weak substrate and inhibitor of P-glycoprotein. The main metabolite of vortioxetine is pharmacologically inactive. Elimination. The mean terminal elimination half-life and oral clearance are 66 hours and 33 L/h, respectively. Approximately 2/3 of the inactive metabolite of vortioxetine is excreted in urine and approximately 1/3 in feces. A small amount of vortioxetine is excreted unchanged in feces. Steady-state plasma concentrations are reached in approximately 2 weeks. Linearity/non-linearity. The pharmacokinetics are linear and time-independent within the studied dose range (2.5-60 mg/day). Based on the AUC0-24h and the terminal elimination half-life, the accumulation index after multiple doses of 5-20 mg/day is 5-6. Special populations. Elderly patients. In elderly healthy subjects (≥65 years; n=20), vortioxetine exposure increased by 27% (Cmax and AUC) compared to a control group of younger healthy subjects (≤45 years) after multiple doses of 10 mg/day. The minimum effective dose of vortioxetine, 5 mg/day, should always be used as the starting dose in patients ≥65 years of age (see "Dosage and Administration"). Doses of vortioxetine greater than 10 mg/day in elderly patients should be administered with caution (see "Special Precautions"). Renal impairment. Compared to a control group of healthy subjects, renal impairment, assessed by the Cockcroft-Gault formula (mild, moderate, or severe; n=8 per group), after a single dose of 10 mg/day of vortioxetine, caused a moderate increase (up to 30%) in vortioxetine exposure. In patients with end-stage renal disease, dialysis caused only a minor reduction in exposure (AUC and Cmax decreased by 13% and 27%, respectively, n=8) after a single 10 mg dose of vortioxetine. Dose adjustment is not required regardless of renal function (see "Dosage and Administration" and "Special Precautions"). Hepatic impairment. The pharmacokinetics of the drug in patients (N=6-8) with mild, moderate, or severe hepatic impairment (Child-Pugh criteria A, B, and C, respectively) were comparable to those in healthy volunteers. AUC change was less than 10% in patients with mild or moderate hepatic impairment and more than 10% in patients with severe hepatic impairment. Cmax change was less than 25% in all groups. Dose adjustment is not required according to hepatic function (see "Dosage and Administration" and "Special Precautions"). CYP2D6 isoenzyme genotype. Vortioxetine plasma concentrations were approximately twice as high in patients with reduced metabolic activity of the CYP2D6 isoenzyme compared to extensive metabolizers. Concomitant use of strong inhibitors of CYP3A4/2C9 isoenzymes in patients with reduced metabolic activity of the CYP2D6 isoenzyme may potentially lead to increased vortioxetine exposure (see "Interactions with other medicinal products and other forms of interaction"). In patients with very rapid metabolism of the CYP2D6 isoenzyme, vortioxetine plasma concentration at 10 mg/day was within the range observed in extensive metabolizers at doses of 5 mg/day and 10 mg/day. Dose adjustment may be considered based on individual patient response (see "Dosage and Administration"). Children and adolescents (under 18 years). The pharmacokinetics of vortioxetine in children and adolescents with major depressive disorder, after single oral administration of 5-20 mg/day, were characterized using population modeling based on data from pharmacokinetic (7-17 years) and efficacy and safety (12-17 years) studies. The pharmacokinetics of vortioxetine in children and adolescents were similar to those in adult patients. Preclinical safety data. In studies of general toxicity in mice, rats, and dogs, vortioxetine administration was mainly associated with CNS effects, including salivation (rats and dogs), pupillary dilation (dogs), and two episodes of seizures in dogs. At the maximum recommended therapeutic dose of 20 mg/day, no convulsive activity was observed, considering a safety margin of 5%. Organic toxicity was limited to the kidneys (rats) and liver (mice and rats). Kidney changes in rats (glomerulonephritis, tubular obstruction, crystals in renal tubules) and liver changes in mice (hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, crystals in bile ducts) were observed at exposures 2 times (rats) and 10 times (mice) the maximum recommended human dose of 20 mg/day. These events were mainly associated with crystal obstruction of renal tubules and bile ducts, characteristic of rodents, and are considered less likely to occur in humans. Vortioxetine did not show genotoxic effects in standard in vitro and in vivo tests. Based on standard 2-year carcinogenicity studies in mice or rats, vortioxetine does not pose a carcinogenic risk to humans. Vortioxetine did not affect fertility, mating ability, reproductive organ function or morphology, or sperm motility in rats. Vortioxetine did not show teratogenic effects in rats or rabbits, although effects on fetal weight and delayed ossification were observed in rats at vortioxetine exposures 10 times the maximum daily dose of 20 mg/day used in humans. Similar effects were observed in rabbits at subtherapeutic exposures. In pre- and postnatal studies in rats, vortioxetine administration at doses that did not cause maternal toxicity and were equivalent to the human dose of 20 mg/day was associated with increased offspring mortality, reduced body weight gain rate, and delayed development (see "Use in pregnancy and lactation"). Vortioxetine was excreted in the milk of lactating rats (see "Use in pregnancy and lactation"). In juvenile toxicity studies in rats, data obtained with vortioxetine therapy were similar to those obtained in adult animals. Environmental risk assessment studies showed that vortioxetine has the potential for persistence, bioaccumulation, and ecotoxicity (risk to fish). However, at the doses recommended for patients, vortioxetine poses a negligible risk to the aquatic and terrestrial environment. Indication for use. BRINTELLIX is indicated for the treatment of major depressive episodes in adults. Contraindications. Hypersensitivity to the active substance or any of the excipients. Concomitant use of non-selective monoamine oxidase inhibitors or selective MAO-A inhibitors (see "Interactions with other medicinal products and other forms of interaction"). Children and adolescents under 18 years of age (safety and efficacy not established). Precautions. Severe renal and hepatic impairment; mania and hypomania; pharmacologically uncontrolled epilepsy, history of seizures; pronounced suicidal behavior; liver cirrhosis; predisposition to bleeding; concomitant use with MAO-B inhibitors (selegiline, rasagiline); serotonergic drugs; drugs that lower the seizure threshold; lithium, tryptophan; St. John's Wort-containing preparations; oral anticoagulants and drugs affecting platelet function; drugs that can cause hyponatremia; electroconvulsive therapy; elderly age. Use in pregnancy and lactation. Pregnancy. Data on the use of vortioxetine in pregnant women are limited. Animal studies have not shown toxic effects on reproductive function (see "Pharmacological Properties"). In neonates whose mothers received serotonergic drugs in late pregnancy, the following symptoms may occur: respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, increased neuro-reflex excitability, irritability, lethargic sleep, persistent crying, somnolence, and poor sleep. These symptoms may be related to both withdrawal syndrome and excessive serotonergic activity. In most cases, such complications begin at birth or later (<24 hours). According to available epidemiological study data, the use of selective serotonin reuptake inhibitors during pregnancy, especially in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although the association of this condition with vortioxetine use has not been studied, given the mechanism of action (increase in serotonin concentration), the potential risk cannot be excluded. Use of BRINTELLIX during pregnancy should only be considered when the expected benefit to the mother outweighs the potential risk to the fetus. Based on reported clinical cases, the risk of postpartum hemorrhage is likely to increase (2-fold) after the use of selective serotonin and norepinephrine reuptake inhibitors in the month preceding delivery. Although no study has investigated the link between postpartum hemorrhage and vortioxetine treatment, there is a potential risk of this event given the relevant mechanism of action (see "Special Precautions"). Breastfeeding. Available preclinical pharmacokinetic and toxicological studies have shown that vortioxetine and its metabolites are excreted in breast milk. Vortioxetine may also be excreted in human breast milk (see "Pharmacological Properties"). The risk to the infant during breastfeeding cannot be excluded. The decision to discontinue breastfeeding or vortioxetine therapy should be made considering the balance of benefits of breastfeeding for the infant and therapy for the mother. Fertility. Fertility studies in female and male rats have shown that vortioxetine does not affect fertility, sperm quality, or mating ability (see "Pharmacological Properties"). In humans, cases of antidepressant use (SSRIs) have shown effects on sperm quality that are reversible. Effects on human fertility have not been observed to date. Dosage and administration. Dosage regimen. The initial and recommended dose of BRINTELLIX in adult patients under 65 years of age is 10 mg once daily. The daily dose may be increased to a maximum dose of 20 mg vortioxetine once daily or decreased to a minimum dose of 5 mg vortioxetine once daily, depending on the individual patient's response. Once depressive symptoms have completely resolved, treatment should be continued for at least 6 months to consolidate the antidepressant effect. Discontinuation of treatment. Patients taking vortioxetine can discontinue the drug abruptly without the need for gradual dose reduction (see "Pharmacological Properties"). Special populations. Elderly patients (≥65 years). In patients ≥65 years of age, the minimum effective dose of BRINTELLIX, 5 mg once daily, should always be used as the starting dose. Caution is required when treating patients ≥65 years with vortioxetine doses greater than 10 mg once daily, as data on the use of the drug in this patient group are limited (see "Special Precautions"). Cytochrome P450 inhibitors. Depending on the individual patient's response, it may be necessary to reduce the dose of BRINTELLIX when adding therapy with strong CYP2D6 isoenzyme inhibitors (e.g., bupropion, quinidine, fluoxetine, paroxetine) (see "Interactions with other medicinal products and other forms of interaction"). Cytochrome P450 inducers. Depending on the individual patient's response, it may be necessary to adjust the dose of BRINTELLIX when adding therapy with a broad spectrum of cytochrome P450 inducers (e.g., rifampicin, carbamazepine, phenytoin) (see "Interactions with other medicinal products and other forms of interaction"). Children and adolescents (under 18 years). The safety and efficacy of BRINTELLIX in children aged 7 to 11 years have not been established. Data are not available for this patient group (see "Special Precautions"). BRINTELLIX should not be used in adolescents aged 12 to 17 years with major depressive disorder, as its efficacy has not been demonstrated in this age group. The safety of BRINTELLIX in adolescents aged 12 to 17 years is described in the "Special Precautions" and "Side Effects" sections. Renal or hepatic impairment. Dose adjustment is not required according to renal or hepatic function (see "Special Precautions" and "Pharmacological Properties"). Method of administration. BRINTELLIX is intended for oral use. Film-coated tablets can be taken independently of meals. Side effects. Characterization of the safety profile. The most frequent adverse reaction was nausea. The list of adverse reactions is provided in the table below. Adverse reactions are classified by frequency as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); frequency unknown (frequency cannot be estimated from available data). The listed list is based on clinical trial data and post-marketing experience. Organ system class Frequency Adverse reactions Immune system disorders Unknown* Anaphylactic reaction Endocrine disorders Unknown* Hyperprolactinemia Metabolism and nutrition disorders Unknown* Hyponatremia Psychiatric disorders Common Unusual dreams Unknown* Insomnia Unknown* Agitation, aggression Nervous system disorders Common Dizziness Unknown* Serotonin syndrome Headache Visual disorders Rare Mydriasis, which may lead to acute angle-closure glaucoma Vascular disorders Uncommon Hot flush Unknown* Bruising (including ecchymosis, purpura, epistaxis, gastrointestinal bleeding, vaginal bleeding) Gastrointestinal disorders Very common Nausea Common Diarrhea, constipation, vomiting Skin and subcutaneous tissue disorders Common Pruritus, including generalized pruritus Hyperhidrosis Uncommon Night sweats Unknown* Angioedema, urticaria, rash *Based on post-marketing experience. Description of individual adverse reactions. Nausea. Nausea was generally mild to moderate in severity and occurred within the first 2 weeks of treatment. Reactions were mostly transient and did not lead to discontinuation of treatment. Gastrointestinal adverse reactions such as nausea were more frequent in women than in men. Elderly patients. For vortioxetine doses of 10 mg or more once daily, the discontinuation rate was higher in patients ≥65 years of age. At vortioxetine doses of 20 mg once daily, the incidence of nausea and constipation was higher in patients ≥65 years (42% and 15%, respectively) compared to patients <65 years (27% and 4%, respectively) (see "Special Precautions"). Sexual dysfunction. In clinical studies, sexual dysfunction was assessed using the Arizona Sexual Experience Scale (ASEX). Doses of 5 to 15 mg did not show data different from placebo. However, vortioxetine 20 mg was associated with an increased incidence of sexual dysfunction (TESD) (see "Pharmacological Properties"). Class-specific effect. Epidemiological studies, mainly involving patients aged 50 and over, have shown an increased risk of bone fractures in patients taking drugs of the corresponding pharmacological class of antidepressants (SSRIs and tricyclic antidepressants). The mechanism causing this risk is unknown, as is whether this risk is associated with vortioxetine intake. Children and adolescents (under 18 years). In total, 308 patients aged 12 to 17 years with major depressive disorder participated in double-blind, placebo-controlled studies of vortioxetine treatment. Overall, the adverse event profile of vortioxetine was similar to that in adults, with the exception of more frequent occurrences of abdominal pain and suicidal ideation in adolescents compared to adults. Overdose. Symptoms. In clinical studies, oral administration of vortioxetine in doses ranging from 40 mg to 75 mg led to an exacerbation of the following adverse reactions: nausea, postural dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and hot flush. Post-marketing experience mainly includes information on vortioxetine overdose up to 80 mg. In most cases, symptoms were absent or mild. The most frequently reported symptoms were nausea and vomiting. Information on overdose with vortioxetine doses exceeding 80 mg is limited. Seizures and serotonin syndrome have been reported after doses several times higher than the therapeutic range. Treatment. In case of overdose, the patient should be monitored and symptomatic treatment provided. Further medical observation in specialized facilities is also recommended. Interactions with other medicinal products and other forms of interaction. Vortioxetine is extensively metabolized in the liver, primarily by oxidation catalyzed by the CYP2D6 isoenzyme and, to a lesser extent, by CYP3A4/5 and CYP2C9 isoenzymes (see "Pharmacological Properties"). Possible effects of other drugs on the pharmacological action of vortioxetine. Irreversible non-selective MAO inhibitors. Due to the risk of serotonin syndrome, concomitant use of vortioxetine with irreversible non-selective MAO inhibitors is contraindicated. Vortioxetine may be initiated at least 14 days after discontinuation of irreversible non-selective MAO inhibitors. Discontinuation of vortioxetine should occur at least 14 days before starting irreversible non-selective MAO inhibitors (see "Contraindications"). Reversible selective MAO-A inhibitors (moclobemide). Concomitant use of vortioxetine and reversible selective MAO-A inhibitors, such as moclobemide, is contraindicated (see "Contraindications"). If concomitant use is deemed necessary, the concomitant drug should be initiated at the minimum dose. Treatment should be conducted under clinical observation for signs of serotonin syndrome (see "Special Precautions"). Reversible non-selective MAO inhibitors (linezolid). Concomitant use of vortioxetine and reversible non-selective MAO inhibitors, such as the antibiotic linezolid, is contraindicated (see "Contraindications"). If concomitant use is deemed necessary, the concomitant drug should be initiated at the minimum dose. Treatment should be conducted under clinical observation for signs of serotonin syndrome (see "Special Precautions"). Irreversible selective MAO-B inhibitors (selegiline, rasagiline). Although the risk of serotonin syndrome is lower with concomitant use of vortioxetine and selective MAO-B inhibitors than with selective MAO-A inhibitors, combined use of vortioxetine and irreversible MAO-B inhibitors, such as selegiline or rasagiline, should be done with caution. If used concomitantly, the patient should be under clinical observation for signs of serotonin syndrome (see "Special Precautions"). Serotonergic drugs. Concomitant use of vortioxetine with other drugs with serotonergic effects, such as opioids (including tramadol) and triptans (including sumatriptan), may lead to serotonin syndrome (see "Special Precautions"). St. John's Wort. Concomitant use of antidepressants and St. John's Wort-containing (Hypericum perforatum) preparations with serotonergic effects may increase the incidence of adverse reactions, including serotonin syndrome (see "Special Precautions"). Drugs that lower the seizure threshold. Antidepressants with serotonergic effects may lower the seizure threshold. Concomitant use with drugs that lower the seizure threshold (e.g., antidepressants (tricyclic antidepressants, selective serotonin and norepinephrine reuptake inhibitors), neuroleptics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion, tramadol) should be done with caution (see "Special Precautions"). ECT (Electroconvulsive Therapy). There is currently no clinical experience with the concomitant use of vortioxetine and ECT, so caution is advised with such use. CYP2D6 isoenzyme inhibitors. In a study of vortioxetine 10 mg/day with bupropion (a strong CYP2D6 isoenzyme inhibitor) at a dose of 150 mg twice daily for 14 days in healthy subjects, vortioxetine exposure (AUC) increased 2.3-fold. Adverse events were more frequent when bupropion was added to ongoing vortioxetine therapy than when vortioxetine was added to ongoing bupropion therapy. Depending on the individual patient's response, dose reduction of vortioxetine should be considered when adding a strong CYP2D6 isoenzyme inhibitor (e.g., bupropion, quinidine, fluoxetine, paroxetine) to ongoing vortioxetine therapy (see "Special Precautions"). CYP3A4, CYP2C9, and CYP2C19 isoenzyme inhibitors. After 6 days of ketoconazole (CYP3A4/5 isoenzyme and P-glycoprotein inhibitor) 400 mg/day or fluconazole (CYP2C9, CYP2C19, and CYP3A4/5 isoenzyme inhibitor) 200 mg/day, vortioxetine exposure (AUC) increased 1.3-fold and 1.5-fold, respectively, when vortioxetine was added in healthy subjects. Dose adjustment is not required. A single dose of omeprazole 40 mg (CYP2C19 isoenzyme inhibitor) did not show inhibitory effects on the pharmacokinetics of multiple doses of vortioxetine in healthy subjects. Interaction in patients with weak CYP2D6 isoenzyme activity. Specific studies of concomitant use of strong CYP3A4 isoenzyme inhibitors (e.g., itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, conivaptan, and many HIV protease inhibitors) and CYP2C9 isoenzyme inhibitors (e.g., fluconazole and amiodarone) in patients with reduced CYP2D6 isoenzyme activity (see "Pharmacological Properties") have not been conducted. However, it is expected that such use in these patients will lead to more pronounced vortioxetine exposure compared to the moderate effects described above. Depending on the individual patient's response, a lower dose of vortioxetine may be necessary with concomitant use of strong CYP3A4 or CYP2C9 isoenzyme inhibitors or in individuals with slow CYP2D6 metabolism. P450 cytochrome inducers. After 10 days of rifampicin (broad-spectrum CYP isoenzyme inducer) 600 mg/day, vortioxetine exposure (AUC) decreased by 72% after a single 20 mg dose of vortioxetine in healthy subjects. Depending on the individual patient's response, dose adjustment of vortioxetine should be considered when adding a strong broad-spectrum P450 cytochrome inducer (e.g., rifampicin, carbamazepine, phenytoin) to ongoing vortioxetine therapy (see "Dosage and Administration"). Alcohol. Concomitant use of single doses of vortioxetine (20 mg and 40 mg) and ethanol (0.6 g/kg) in healthy subjects did not result in significant pharmacokinetic changes of vortioxetine or ethanol, or significant impairment of cognitive functions compared to placebo. However, alcohol consumption is not recommended during antidepressant therapy. Acetylsalicylic acid. A single dose of acetylsalicylic acid 150 mg/day did not alter the pharmacokinetics of multiple doses of vortioxetine in healthy subjects. Possible effects of vortioxetine on the pharmacological action of other drugs. Anticoagulants and antiplatelet agents. Compared to placebo, vortioxetine did not show significant effects on prothrombin parameters, international normalized ratio (INR), or R-/S-warfarin ratio in plasma during concomitant use of multiple doses of vortioxetine and fixed doses of warfarin in healthy subjects. Similarly, compared to placebo, vortioxetine did not show significant inhibitory effects on platelet aggregation or on the pharmacokinetics of acetylsalicylic acid and salicylic acid after multiple doses of vortioxetine with concomitant use of acetylsalicylic acid 150 mg/day in healthy subjects. Nevertheless, caution should be exercised with concomitant use of vortioxetine and oral anticoagulants or antiplatelet agents due to the potential risk of bleeding due to pharmacodynamic interactions (see "Special Precautions"). P450 cytochrome substrates. In vitro studies have not shown vortioxetine's ability to inhibit or induce P450 cytochrome system isoenzymes (see "Pharmacological Properties"). After multiple doses of vortioxetine in healthy subjects, no inhibitory effects on the activity of P450 cytochrome system isoenzymes CYP2C19 (omeprazole, diazepam), CYP3A4/5 (ethinylestradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (tolbutamide, S-warfarin), CYP1A2 (caffeine), or CYP2D6 (dextromethorphan) were observed. No pharmacodynamic interactions were observed either. No significant impairment of cognitive function was observed compared to placebo during combined use of vortioxetine and a single dose of diazepam 10 mg. Compared to placebo, no significant effect of vortioxetine on sex hormone levels was observed during concomitant use with oral combined contraceptives (ethinylestradiol 30 mcg + levonorgestrel 150 mcg). Lithium, tryptophan. No clinically significant changes were observed in healthy subjects during concomitant use of multiple doses of lithium and vortioxetine. However, given that cases of potentiation of serotonergic antidepressant effects have been described with concomitant use of lithium or tryptophan, combined use of vortioxetine with these drugs should be done with caution. Effect on urine screening results for drug detection. Cases of false-positive urine immunoassay results for methadone have been reported in patients taking vortioxetine. Urine screening results for drugs should be interpreted with caution, and alternative analytical methods (e.g., chromatographic methods) should be considered to confirm the results. Special precautions. Use in children and adolescents under 18 years of age. The use of BRINTELLIX is not recommended for the treatment of depression in children aged 7 to 11 years, as the safety and efficacy of vortioxetine have not been established in this age group (see "Dosage and Administration"). BRINTELLIX should not be used in adolescents aged 12 to 17 years with major depressive disorder, as its efficacy has not been demonstrated (see "Pharmacodynamics"). In general, the adverse event profile of vortioxetine in adolescents was similar to that in adult patients, with the exception of more frequent occurrences of abdominal pain and suicidal ideation in adolescents compared to adults (see "Pharmacodynamics" and "Side Effects"). In clinical trials in children and adolescents receiving antidepressants, suicidal behavior (suicidal attempts and suicidal ideation) and hostility (predominantly aggressive behavior, tendency to opposition and irritability) were more frequent compared to the placebo group. Suicide/suicidal ideation or clinical worsening of depression is associated with an increased risk of suicidal ideation, self-harm, and suicide (suicidal behavior). This risk persists until significant remission is achieved. Since improvement may not be observed for the first few weeks of therapy or even longer, patients should be under continuous observation until their condition improves. General clinical practice shows that the risk of suicide may increase in the early stages of recovery. Patients with a history of suicidal behavior or patients with significant suicidal ideation are at higher risk of suicidal ideation or suicide attempts, so they require close monitoring during treatment. In adult patients with mental disorders, a meta-analysis of placebo-controlled clinical trials showed an increased risk of suicidal behavior in patients under 25 years of age compared to placebo when using antidepressants. Patients require close monitoring, especially those at high risk of suicide, particularly at the beginning of treatment or when the drug dose is changed. Patients (and their caregivers) should be warned to pay attention to any signs of clinical worsening, development of suicidal behavior and suicidal ideation, as well as unusual changes in behavior, and to seek immediate medical attention if such symptoms develop. Seizures. There is a risk of seizures when using antidepressants. Therefore, vortioxetine should be used with caution in patients with a history of seizures or in patients with unstable epilepsy (see "Interactions with other medicinal products"). If seizures occur or their frequency increases, vortioxetine treatment should be discontinued. Serotonin syndrome or neuroleptic malignant syndrome. Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS) are potentially life-threatening conditions that can develop with vortioxetine use. The risk of developing SS and NMS increases with concomitant use of serotonergic drugs (including opioids and triptans), drugs affecting serotonin metabolism (including SSRIs), antipsychotics, or other dopamine antagonists. Patients should be monitored for objective and subjective symptoms of SS or NMS (see "Contraindications" and "Interactions with other medicinal products and other forms of interaction"). Symptoms of serotonin syndrome include changes in mental status (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). If such symptoms develop, vortioxetine therapy should be discontinued immediately and symptomatic treatment initiated. Mania/hypomania. Vortioxetine should be used with caution in patients with a history of manic/hypomanic episodes. The drug should be discontinued if a manic state develops. Aggression/agitation. Patients treated with antidepressants, including vortioxetine, may also experience feelings of aggression, anger, agitation, and irritability. The patient's condition and disease status should be monitored. Patients (and their caregivers) should be warned to consult a doctor if aggressive behavior or agitation develops or if the condition worsens. Bleeding. Rare cases of hemorrhagic disorders, such as ecchymosis, purpura, gastrointestinal, and gynecological bleeding, have been reported with the use of serotonergic antidepressants, including vortioxetine. Selective serotonin and norepinephrine reuptake inhibitors, including vortioxetine, may also increase the risk of postpartum hemorrhage (see "Use in pregnancy and lactation"). The drug is recommended for use with caution in patients taking anticoagulants and/or drugs affecting platelet function (e.g., atypical antipsychotics, phenothiazines, most tricyclic antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs), and acetylsalicylic acid), as well as in patients with a known predisposition to bleeding/coagulation disorders (see "Interactions with other medicinal products and other forms of interaction"). Hyponatremia. Rare cases of hyponatremia have been reported with the use of serotonergic antidepressants (selective serotonin and norepinephrine reuptuptake inhibitors), possibly due to the syndrome of inappropriate secretion of antidiuretic hormone. Caution should be exercised when using vortioxetine in high-risk groups, such as elderly patients, patients with liver cirrhosis, or patients taking concomitant medications that may cause hyponatremia. If possible, vortioxetine should be discontinued in patients with symptomatic hyponatremia, and appropriate medical intervention should be initiated to correct their condition. Glaucoma. Cases of pupillary dilation have been reported with antidepressant use, including vortioxetine. This effect can lead to a reduction in the angle of vision, followed by an increase in intraocular pressure and the development of angle-closure glaucoma. Vortioxetine should be used with caution in patients with elevated intraocular pressure and those at risk of developing acute angle-closure glaucoma. Elderly patients. Data on the use of BRINTELLIX in elderly patients with major depressive episodes are limited. Therefore, caution should be exercised when treating patients ≥65 years with vortioxetine doses greater than 10 mg once daily (see "Dosage and Administration", "Pharmacological Properties", and "Side Effects"). Renal or hepatic impairment. Given that patients with renal or hepatic impairment are at risk, and considering that data on the use of BRINTELLIX in this subgroup are limited, caution should be exercised when treating such patients (see "Dosage and Administration" and "Pharmacological Properties"). BRINTELLIX contains sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, meaning it is essentially "sodium-free". Effects on ability to drive and use machines. BRINTELLIX has no or negligible influence on the ability to drive and use machines. However, since adverse reactions such as dizziness have been reported, patients should exercise caution when driving or operating machinery, especially at the beginning of vortioxetine treatment or when changing its dose. Dosage form. Film-coated tablets 5 mg, 10 mg, 15 mg, and 20 mg. 14 tablets in PVC/PVDC and aluminum foil blister packs. 1 or 2 blisters with instructions for use in a cardboard box with a tamper-evident closure mechanism with a perforated tear strip for initial opening control. Storage conditions. Not exceeding 25°C. Keep out of reach of children. Shelf life: 4 years. Do not use after the expiry date indicated on the packaging. Dispensing conditions: Pharmaceutical product group - II, dispensed by prescription form No. 3.