Brintellix, 20 mg 28 pcs.

Mechanism of Action

The mechanism of action of vortioxetine appears to be related to its direct modulating serotonergic activity and inhibition of the serotonin transporter protein.

Preclinical studies show that vortioxetine acts as an antagonist of 5-HT₃, 5-HT₇ and 5-HT_1D receptors, a partial agonist of 5-HT_1B receptors and a full agonist of 5-HT_1A receptors, and also inhibits the 5-HT transporter, thereby modulating neurotransmission in several systems, primarily serotonergic, but probably also noradrenergic, dopaminergic, histamine-mediated neurotransmission, acetylcholine, GABA and glutamate.

This multimodal pharmacological activity appears to underlie the antidepressant and anxiolytic properties of vortioxetine, and determines the improvement in cognitive function, learning and memory observed in animal studies.

However, because the individual contribution of each pharmacological target to the observed pharmacodynamic profile of vortioxetine remains unclear, extrapolation of the reported preclinical data to humans should be done with caution.

Two studies using positron emission tomography (PET) in humans to quantify the occupancy of 5-HT transporters (using ligands ¹¹C-MADAM or ¹¹C-DASB), at different levels of vortioxetine dosing, the following findings were obtained: The average number of 5-HT transporters associated with vortioxetine was approximately 50% at the 5 mg/day dose, 65% at the 10 mg/day dose, and increased to 80% when the dose was increased to 20 mg/day.

Clinical efficacy and safety

The efficacy and safety of vortioxetine have been studied in a number of clinical trials involving more than 6,700 patients, of which more than 3,700 patients participated in short-term (≤12 weeks) studies in major depressive disorder (MDD).

Twelve double-blind, placebo-controlled, 6/8-week, fixed-dose studies were conducted to determine the short-term effectiveness of vortioxetine in MDD in adult patients (including elderly patients).

The efficacy of vortioxetine has been demonstrated in at least a single-dose group in 9 of 12 studies, where a change of at least 2 points from placebo was shown on the Montgomery-Asberg Depression Rating Scale (MADRS) and Hamilton Depression Scale (HAM-D24).

This was clinically confirmed by the number of patients who responded to therapy and achieved remission as well as improvement on the General Clinical Impression Scale (CGI-I). The efficacy of vortioxetine increased with increasing dose.

The efficacy of individual studies was confirmed by a meta-analysis (MMRM) of mean changes in overall MADRS score at 6/8 weeks in short-term placebo-controlled studies in adults.

In the meta-analysis of these studies, the differences from placebo were statistically significant: -2.3 points (p=0.007); -3.6 points (p< 0.001); -4.6 points (p< 0.001) at doses of 5, 10 and 20 mg/day, respectively; at the 15 mg/day dose no statistically significant differences with placebo were achieved by the meta-analysis, but the mean differences with placebo were -2.6 points.

The efficacy of vortioxetine was also confirmed in the pooled analysis, in which the response rate was 46% to 49% with vortioxetine compared with 34% with placebo (p< 0.01; NRI analysis).

In addition, vortioxetine in the 5 to 20 mg/day dose range demonstrated efficacy across a broad spectrum of depression symptoms (as assessed by changes in scores on all individual MADRS subscales).

The efficacy of vortioxetine at doses of 10 or 20 mg/day was also shown in a 12-week, double-blind, variable-dose comparative study with agomelatine at doses of 25 or 50 mg/day in patients with MDD. Vortioxetine demonstrated statistically significant superiority over agomelatine on the overall MADRS score, which was also clinically significant in the number of patients responding to therapy who achieved remission and improvement on the CGI-I scale.

Supportive therapy

The persistence of antidepressant effect with supportive therapy has been shown in the relapse prevention study.

Patients who were in remission after initial vortioxetine therapy in a 12-week open-label study were randomized to vortioxetine 5 or 10 mg/day or placebo groups and monitored for relapse during a double-blind follow-up period of at least 24 weeks (24 to 64 weeks).

Vortioxetine outperformed placebo (p=0.004) on the primary assessment criterion, time to MDD relapse, with a risk ratio of 2.0; this means that the risk of relapse was twice as high in the placebo group as in the vortioxetine group.

Elderly patients

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

Patients with severe depression or with depression and high levels of anxiety

The efficacy of vortioxetine has also been demonstrated in patients with severe depression (baseline MADRS total score ≥30) and in patients with depression with concomitant high anxiety (baseline HAM-A total score ≥20) in short-term studies of adult patients (mean difference from placebo on the MADRS scale at weeks 6 and 8 ranged from 2.8 to 7.3 points and from 3.6 to 7.3 points, respectively (MMRM analysis).

In a separate study in the elderly, vortioxetine also showed efficacy in this group of patients.
The persistence of the antidepressant effect in this patient population has also been shown in a long-term relapse prevention study.

Effect of vortioxetine on the Digit Symbol Substitution Test (DSST), the University of California San Diego (UPSA) Basic Life Skills Scale (objective measures), and the Perceived Deficits Questionnaire (PDQ) and the Cognitive and Physical Functioning Questionnaire (CPFQ) (subjective measures).

The efficacy of vortioxetine (at a dose of 5-20 mg/day) in patients with PD has been studied in two short-term placebo-controlled studies in adults and in one in older patients.

Vortioxetine had a statistically significant effect on the Digital Character Substitution Test (DSST) compared with placebo, with Δ = 1.75 (p = 0.019) to 4.26 (p < 0.0001) in two studies in adults and Δ = 2.79 (p = 0.023) in the study in older patients.

In a meta-analysis (ANCOVA, LOCF) of the mean change from the number of correct characters in the DSST compared to baseline in all three studies, vortioxetine differed from placebo (p < 0.05) with a standardized effect size of 0.35. When adjusted for the change in MADRS, the total score in the meta-analysis of the same studies showed that vortioxetine differed from placebo (p < 0.05) with a standardized effect value of 0.24.

One study evaluated the effect of vortioxetine on functional ability using the University of California San Diego (UCSD) Quality of Life Essential Skills Assessment (UPSA).

Vortioxetine was statistically significantly different from placebo with a score of 8.0 for vortioxetine versus 5.1 for placebo (p = 0.0003).

In one study, vortioxetine outperformed placebo on subjective measures measured by the subjective deficit questionnaire, with results of -14.6 for vortioxetine and -10.5 for placebo (p = 0.002).

Vortioxetine did not differ from placebo with respect to subjective measures measured by the Cognitive and Physical Functioning Assessment Questionnaire, with results of -8.1 for vortioxetine versus -6.9 for placebo (p = 0.086).

Tolerability and safety

Safety and tolerability of vortioxetine have been established in short- and long-term studies in the dose range of 5 to 20 mg/day. Information about adverse reactions is presented in the section “Adverse effects”.

Vortioxetine did not increase the incidence of insomnia or drowsiness compared to placebo.

Short- and long-term placebo-controlled clinical trials have consistently evaluated possible withdrawal symptoms after abrupt discontinuation of vortioxetine treatment.

There was no clinically significant difference with placebo in the incidence or quality of withdrawal symptoms after both short-term (6-12 weeks) and long-term (24-64 weeks) vortioxetine therapy.

The incidence of spontaneous complaints of sexual adverse reactions was low and similar to placebo in both short-term and long-term vortioxetine studies. In studies using the Arizona Sexual Function Scale (ASEX), the incidence of therapy-induced sexual dysfunction (TESD) and total ASEX score were not clinically significantly different from placebo when vortioxetine was used at doses of 5-15 mg/day.

An increased incidence of sexual dysfunction was observed with vortioxetine at a dose of 20 mg/day compared with placebo (frequency difference 14.2%, 95% CI (1.4; 27.0)).

In short- and long-term studies, vortioxetine did not affect body weight, heart rate, or blood pressure compared with placebo.

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

In patients with MDD, vortioxetine had no clinically significant effect on ECG parameters, including QT, QTc, PR and QRS intervals. In a careful study of the QTc interval in healthy subjects, vortioxetine at doses up to 40 mg/day had no effect on its duration.

Pharmacokinetics

Intake

Vortioxetine is slowly but well absorbed after oral administration. Maximum plasma concentration is reached in 7 – 11 h. After multiple doses of 5, 10 or 20 mg/day the mean maximum plasma concentration (Cmax) is 9-33 ng/ml. Absolute bioavailability is 75%. Food intake has no effect on the pharmacokinetics of the drug (see section “Dosage and administration”).

Distribution

The average volume of distribution (Vss) is 2600 l, indicating extensive extravascular distribution. The degree of binding to plasma proteins is high (98-99%) and appears to be independent of the plasma concentration of vortioxetine.

Biotransformation

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

In drug interaction studies, no inhibitory or inducing effects of vortioxetine on the CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5 isoenzymes were found (see section “Interaction with other medicinal products”). Vortioxetine is a weak inhibitor and substrate of P-glycoprotein.
The main metabolite of vortioxetine is pharmacologically inactive.

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

Linearity/nonlinearity

Pharmacokinetics are linear and time-independent in the dose range studied (2.5-60 mg/day).
According to the half-life based on AUC_o-24h after multiple doses of 5-20 mg/day, the accumulation index is 5 to 6.

Particular patient groups

Elderly patients

In elderly healthy subjects (≥65 years; n=20), vortioxetine exposure was increased by 27% (Cmax and AUC) compared with a control group of young 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 an initial dose in patients aged ≥65 years (see section “Dosage and administration”). Caution should be exercised when prescribing vortioxetine doses above 10 mg/day in elderly patients (see section “Special Precautions”).

Renal Impairment
After a single dose of 10 mg vortioxetine, renal impairment assessed by the Cockcroft-Gault formula (mild, moderate, or severe; n=8 per group) resulted in a moderate (up to 30%) increase in vortioxetine exposure compared to a control group of healthy subjects.

In patients with end-stage renal disease, dialysis resulted in only a slight decrease in exposure (AUC and Cmax decreased by 13% and 27%, respectively; n=8) after a single dose of 10 mg vortioxetine. No dose adjustment is required (see section “Special Precautions”).

Hepatic impairment

There were no changes in the pharmacokinetics of vortioxetine after a single dose of vortioxetine 10 mg in patients with mild to moderate hepatic impairment (Child-Pugh criteria A or B; n=8 per group) (less than 10% change in AUC). No dose adjustment is required (see section “Dosage and administration”).

Vortioxetine has not been studied in patients with severe hepatic impairment; therefore, the drug should be used with caution in these patients (see section “Cautions”).

CYP2D6 isoenzyme gene types

The plasma concentration of vortioxetine was approximately twice as high in patients with decreased CYP2D6 isoenzyme metabolism compared to extensively metabolized patients. Concomitant use of strong CYP3A4/2C9 isoenzyme inhibitors in patients with decreased CYP2D6 isoenzyme metabolic activity may potentially lead to increased vortioxetine exposure (see section “Interaction with other medicinal products”).

In patients with extremely rapid metabolism of the CYP2D6 isoenzyme, plasma concentrations of 10 mg/day vortioxetine were within the range of values obtained in extensive metabolizers at doses of 5 mg/day and 10 mg/day. As in all patients, dose adjustments should be considered depending on the individual response (see section “Dosage and administration”).

Preclinical safety data

In general toxicity studies, administration of vortioxetine in mice, rats, and dogs was accompanied by effects primarily on the CNS, which included manifestations such as salivation (rats and dogs), dilated pupils (dogs), and two episodes of seizures in dogs.

No seizure activity was reported at the maximum recommended therapeutic dose of 20 mg/day, given that the safety limit is set at 5%. Organ toxicity was limited to the kidneys (rats) and liver (mice and rats).

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

Vortioxetine had no genotoxic effects in a standard battery of in vitro and in vivo tests.

Based on results of standard two-year carcinogenicity studies in mice or rats, vortioxetine has no risk of carcinogenicity in humans.

Vortioxetine had no effect on fertility, mating ability, reproductive organ function, or sperm morphology and motility in rats.

Vortioxetine had no teratogenic effects in rats or rabbits, although effects on fetal weight and delayed ossification were noted in rats at doses of vortioxetine 10 times the maximum daily human dose of 20 mg/day. Similar effects were observed in rabbits at subtherapeutic exposure.

In pre- and postnatal studies in rats, use of vortioxetine at doses that had no toxic effects on the mother and matched the 20 mg/day dose in humans was associated with increased infant mortality, decreased rate of weight gain, and delayed development (see “Pregnancy and Breastfeeding Applications”).

Vortioxetine penetrated the milk of lactating rats (see “Administration in pregnancy and breastfeeding”).

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

The active ingredient vortioxetine hydrobromide is classified as a PBT substance (persistent, bioaccumulable and toxic; risk to fish). However, vortioxetine poses little risk to aquatic and terrestrial environments at patient-recommended doses.

Indications

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

Pharmacological effect

Mechanism of action

The mechanism of action of vortioxetine appears to be related to its direct modulating serotonergic activity and inhibition of the serotonin transport protein.

Preclinical studies indicate that vortioxetine acts as an antagonist at the 5-HT3, 5-HT7 and 5-HT1D receptors, a partial agonist at the 5-HT1B receptor, and a full agonist at the 5-HT 1A receptor.
receptors, and also inhibits the 5-HT transporter, thereby modulating neurotransmission in several systems, primarily serotonergic, but probably also noradrenergic, dopaminergic, neurotransmission mediated by histamine, acetylcholine, GABA and glutamate.

This multimodal pharmacological activity appears to underlie the antidepressant and anxiolytic properties of vortioxetine and is also responsible for the improvements in cognition, learning and memory observed in animal studies.

However, since the individual contribution of each pharmacological target to the observed pharmacodynamic profile of vortioxetine remains unclear, extrapolation of the reported preclinical data to humans should be done with caution.

Two studies using positron emission tomography (PET) in humans to quantify the extent of 5-HT transporter occupancy (using ligands 11C-MADAM or 11C-DASB), at different dosage levels of vortioxetine, reported the following data: the average number 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% when the dose was increased to 20 mg/day.

Clinical efficacy and safety

The efficacy and safety of vortioxetine have been studied in a number of clinical studies involving more than 6,700 patients, of which more than 3,700 patients participated in short-term (≤12 weeks) studies in major depressive disorder (MDD).

Twelve double-blind, placebo-controlled, 6/8-week, fixed-dose studies were conducted to determine the short-term effectiveness of vortioxetine for MDD in adult patients (including elderly patients).

Efficacy of vortioxetine was demonstrated in at least the single-dose group in 9 of 12 studies, showing a change of at least 2 points from placebo 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 responding to therapy and achieving remission, as well as improvement on the Clinical Global Impression Scale (CGI-I). The effectiveness of vortioxetine increased with increasing dose.

Individual study efficacy was supported by a meta-analysis (MMRM) of mean changes in MADRS total score at 6/8 weeks in short-term placebo-controlled studies in adults.

According to the results of a meta-analysis of these studies, the differences from placebo were statistically significant: -2.3 points (p = 0.007); -3.6 points (p<0.001); -4.6 points (p<0.001) at doses of 5, 10 and 20 mg/day, respectively; at a dose of 15 mg/day, statistically significant differences from placebo were not achieved according to the meta-analysis, but the average difference compared to placebo was -2.6 points.

The effectiveness of vortioxetine was also confirmed in the pooled analysis, in which the response rate was 46% to 49% with vortioxetine compared with 34% with placebo (p < 0.01; NRI analysis).

In addition, vortioxetine in the dose range of 5 to 20 mg/day has demonstrated effectiveness against a wide range of depressive symptoms (assessed by change in scores on all individual MADRS subscales).

The effectiveness of vortioxetine at doses of 10 or 20 mg/day was also shown in a 12-week, double-blind, dose-controlled comparative study with agomelatine at doses of 25 or 50 mg/day in patients with MDD. Vortioxetine demonstrated statistically significant superiority over agomelatine in terms of the total MADRS score, which was also clinically significant in the number of patients who responded to therapy, achieved remission and improvement on the CGI-I scale.

Maintenance therapy

The durability of the antidepressant effect with maintenance therapy was shown in a relapse prevention study.

Patients in remission after initial vortioxetine therapy in the 12-week open-label study were randomized to vortioxetine 5 or 10 mg/day or placebo and monitored for relapse during a double-blind observation period of at least 24 weeks (range 24 to 64 weeks).

Vortioxetine was superior to placebo (p=0.004) for the primary outcome measure of time to relapse of MDD, with a hazard ratio of 2.0; this means that the risk of relapse was twice as high in the placebo group than in the vortioxetine group.

Elderly patients

In a double-blind, placebo-controlled, 8-week, fixed-dose study in elderly patients with depression (≥65 years, n=452, 156 of whom were treated with vortioxetine), vortioxetine 5 mg/day was superior to placebo as assessed by total MADRS and HAM-D24 scores. The difference between vortioxetine and placebo was 4.7 points on the MADRS at week 8 of treatment (MMRM analysis).

Patients with severe depression or depression and high levels of anxiety

The effectiveness of vortioxetine has also been demonstrated in patients with severe depression (baseline MADRS total score ≥30) and in patients with depression with concomitant high levels of anxiety (baseline HAM-A total score ≥20) in short-term studies of adult patients (mean difference from placebo on MADRS at weeks 6 and 8 ranged from 2.8 to 7.3 points and from 3.6 up to 7.3 points respectively (MMRM analysis)).

In a separate study in elderly patients, vortioxetine was also effective in this group of patients.
The persistence of the antidepressant effect in this category of patients was also shown in a long-term relapse prevention study.

Effect of vortioxetine on the Digit Symbol Substitution Test (DSST), the UC San Diego Life Skills Assessment (UPSA) (objective measures), and Perceived Deficits Questionnaire (PDQ) scores and Cognitive and Physical Functioning Questionnaire (CPFQ) scores (subjective measures). indicators).

The effectiveness of vortioxetine (at a dose of 5-20 mg/day) in patients with MDD was studied in two short-term placebo-controlled studies in adults and one in elderly patients.

Vortioxetine had a statistically significant effect on the Digit Symbol Substitution Test (DSST) compared with placebo, with Δ = 1.75 (p = 0.019) to 4.26 (p < 0.0001) in two studies in adults and Δ = 2.79 (p = 0.023) in a study in elderly patients.

In a meta-analysis (ANCOVA, LOCF) of mean change from baseline in number of characters correct on the DSST in all three studies, vortioxetine differed from placebo (p < 0.05) with a standardized effect size of 0.35. When adjusted for change in MADRS, total scores in a 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 ability using the University of California San Diego Life Skills Assessment (UPSA).

Vortioxetine was statistically significantly different from placebo with results of 8.0 points for vortioxetine versus 5.1 points for placebo (p = 0.0003).

In one study, vortioxetine was superior to placebo on subjective scores as measured by the Subjective Deficit Questionnaire, with results of -14.6 for vortioxetine and -10.5 for placebo (p = 0.002).

Vortioxetine did not differ from placebo on subjective scores measured by the Cognitive and Physical Functioning Questionnaire, with results of -8.1 for vortioxetine versus -6.9 for placebo (p = 0.086).

Portability and safety

The safety and tolerability of vortioxetine have been established in short-term and long-term studies over a dose range of 5 to 20 mg/day. Information about unwanted side reactions is presented in the “Side Effects” section.

Vortioxetine did not increase the incidence of insomnia or somnolence compared with placebo.

Short-term and long-term placebo-controlled clinical studies have consistently assessed potential withdrawal symptoms following abrupt cessation of vortioxetine treatment.

There was no clinically significant difference from placebo in the incidence or quality of withdrawal symptoms after either short-term (6-12 weeks) or long-term (24-64 weeks) vortioxetine therapy.

The incidence of spontaneous complaints of sexual adverse reactions was low and similar to placebo in both short-term and long-term studies of vortioxetine. In studies using the Arizona Sexual Function Scale (ASEX), the incidence of treatment-induced sexual dysfunction (TESD) and total ASEX scores were not clinically significantly different from placebo when vortioxetine was used at doses of 5-15 mg/day.

When using vortioxetine at a dose of 20 mg/day, an increase in the incidence of sexual dysfunction was observed compared with placebo (difference in frequency 14.2%, CI 95% (1.4, 27.0)).

In short- and long-term studies, vortioxetine had no effect on weight, heart rate, or blood pressure compared with placebo.

Vortioxetine did not have a clinically significant effect on parameters of liver and kidney function in clinical studies.

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

Pharmacokinetics

Suction

Vortioxetine is slowly but well absorbed after oral administration. The maximum plasma concentration is achieved after 7 – 11 hours. After repeated use in doses of 5, 10 or 20 mg / day, the average maximum plasma concentration (Cmax) is 9-33 ng/ml. Absolute bioavailability is 75%. Food intake does not affect the pharmacokinetics of the drug (see section “Method of administration and dosage”).

Distribution

The mean volume of distribution (Vss) is 2600 L, indicating extensive extravascular distribution. The degree of binding to plasma proteins is high (98-99%) and does not appear to depend on the concentration of vortioxetine in plasma.

Biotransformation

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

Drug interaction studies did not reveal an inhibitory or inducing effect of vortioxetine on the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4/5 (see section “Interaction with other drugs”). Vortioxetine is a weak inhibitor and substrate of P-glycoprotein.
The main metabolite of vortioxetine is pharmacologically inactive.

Removal
The average half-life and oral clearance are 66 hours and 33 l/hour, respectively. About 2/3 of the inactive metabolite vortioxetine is excreted in the urine and about 1/3 in the feces. Only a small amount of vortioxetine is excreted unchanged in the feces. Steady-state plasma concentrations are achieved after approximately 2 weeks.

Linearity/nonlinearity

Pharmacokinetics is linear and does not depend on time in the dose range studied (2.5-60 mg/day).
Based on the half-life based on AUCo-24h after multiple doses of 5-20 mg/day, the accumulation index is 5 to 6.

Special patient groups

Elderly patients

In elderly healthy subjects (≥65 years; n=20), vortioxetine exposure was increased by 27% (Cmax and AUC) compared to a control group of young healthy subjects (≤45 years) after repeated doses of 10 mg/day.

The minimum effective dose of vortioxetine 5 mg/day should always be used as an initial dose in patients aged ≥65 years (see Dosage and Administration). Vortioxetine should be prescribed with caution to elderly patients at doses above 10 mg/day (see section “Special Instructions”).

Kidney failure
Following a single 10 mg dose of vortioxetine, renal impairment assessed by the Cockcroft-Gault formula (mild, moderate or severe; n=8 per group) resulted in a modest (up to 30%) increase in vortioxetine exposure compared with healthy control subjects.

In patients with end-stage renal disease, dialysis resulted in only a small reduction in exposure (AUC and Cmax decreased by 13% and 27%, respectively; n=8) following a single dose of vortioxetine 10 mg. No dose adjustment is required (see section “Special Instructions”).

Liver failure

Following a single 10 mg dose of vortioxetine in patients with mild to moderate hepatic impairment (Child-Pugh A or B; n=8 per group), no change in vortioxetine pharmacokinetics was observed (less than 10% change in AUC). No dose adjustment is required (see section “Method of administration and dosage”).

Vortioxetine has not been studied in patients with severe hepatic impairment, so the drug should be used with caution in such patients (see section “Special Instructions”).

Types of CYP2D6 isoenzyme genes

Plasma concentrations of vortioxetine were approximately two times higher in patients with reduced metabolic activity of the CYP2D6 isoenzyme compared with 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 exposure to vortioxetine (see section “Interaction with other drugs”).

In patients with extremely rapid metabolism of the CYP2D6 isoenzyme, plasma concentrations of vortioxetine 10 mg/day were within the range of values ​​obtained in extensive metabolizers at doses of 5 mg/day and 10 mg/day. As for all patients, depending on the individual response, the possibility of adjusting the dose of the drug should be considered (see section “Dosage and Administration”).

Preclinical safety data

In general toxicity studies, vortioxetine administration in mice, rats and dogs was associated with primarily CNS effects, which included salivation (rats and dogs), dilated pupils (dogs), and two episodes of seizures in dogs.

When the drug was administered at the maximum recommended therapeutic dose of 20 mg/day, no seizure activity was recorded, taking into account that the safety limit was defined as 5%. Organ toxicity was limited to the kidney (rats) and liver (mice and rats).

Changes in the kidneys in rats (glomerulonephritis, tubular obstruction, crystals in the renal tubules) and liver in mice and rats (hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, crystals in the bile ducts) were observed at exposures greater than 2 times (rats) and 10 times (mice) the human dose at the maximum recommended dose of 20 mg/day These cases have been associated primarily with rodent-specific crystal obstruction of the renal tubules and bile ducts and are considered unlikely to occur in humans.

Vortioxetine was not genotoxic in a standard battery of in vitro and in vivo tests.

Based on standard 2-year carcinogenicity studies in mice or rats, vortioxetine does not appear to have a risk of carcinogenicity in humans.

Vortioxetine had no effect on fertility, mating ability, reproductive organ function, or sperm morphology and motility in rats.

Vortioxetine was not teratogenic in rats or rabbits, although effects on fetal weight and delayed ossification were observed in rats with exposure to vortioxetine doses exceeding 10 times the maximum human daily dose of 20 mg/day. Similar effects were observed in rabbits with subtherapeutic exposure.

In pre- and postnatal studies in rats, the use of vortioxetine in doses that did not have toxic effects on the mother and corresponded to a dose of 20 mg / day in humans was associated with increased mortality of pups, a decrease in the rate of body weight gain and a slowdown in their development (see section “Use during pregnancy and lactation”).

Vortioxetine penetrated into the milk of lactating rats (see section “Use during pregnancy and breastfeeding”).

In juvenile toxicity studies in rats, data obtained from vortioxetine therapy were correlated with those obtained in adult animals.

The active substance vortioxetine hydrobromide is classified as a PBT substance (persistent, bioaccumulative and toxic; risk to fish). However, at recommended patient doses, vortioxetine poses a negligible risk to the aquatic and terrestrial environment.

Special instructions

Use in children and adolescents under 18 years of age

Brintellix is ​​not recommended for the treatment of depression in patients under 18 years of age, since the safety and effectiveness of vortioxetine in this age group have not been established (see section “Dosage and Administration”).

In clinical studies, children and adolescents receiving other antidepressants were more likely to experience suicidal behavior (suicidal attempts and suicidal ideation) and hostility (with a predominance of aggressive behavior, confrontational behavior, and irritability) compared with those receiving placebo.

Suicide/suicidal ideation or clinical deterioration

Depression is associated with an increased risk of suicidal ideation, self-harm, and suicide (suicidal behavior).

This risk persists until significant remission occurs. Since improvement may not be observed during the first few weeks of therapy or even longer, patients should be closely monitored until their condition improves.

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

Patients with a history of suicidal behavior or patients with significant levels of suicidal ideation before treatment are at greater risk for suicidal ideation or suicide attempts and should be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with mental disorders showed that there is an increased risk of suicidal behavior when using antidepressants in patients under 25 years of age compared with placebo.

Patients require careful monitoring, especially those who are at high risk of suicide, especially at the beginning of treatment or when the dose of the drug is changed. Patients (and their caregivers) should be cautioned to monitor for signs of any clinical deterioration, suicidal behavior and ideation, or unusual changes in behavior, and to seek immediate medical attention if such symptoms occur.

Seizures

There is a possible risk of developing seizures when using antidepressants. Therefore, Brintellix should be used with caution in patients with a history of seizures or in patients with unstable epilepsy (see section “Interactions with other drugs”). If seizures occur or their frequency increases, treatment with vortioxetine should be discontinued.

Serotonin syndrome or neuroleptic malignant syndrome

Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS) are potentially life-threatening conditions that may occur with use of Brintellix.

The risk of developing SS or NMS is increased when used concomitantly with serotonergic drugs (including triptans), drugs that affect serotonin metabolism (including MAOIs), antipsychotics, or other dopamine antagonists. Patients should be monitored for the occurrence of objective and subjective symptoms of SS and NMS (see sections “Contraindications” and “Interaction with other drugs”).

Symptoms of serotonin syndrome include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, blood pressure lability, hyperthermia), neuromuscular abnormalities (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). If such symptoms occur, therapy with Brintellix should be stopped immediately and symptomatic treatment should be initiated.

Mania/hypomania
Brintellix should be used with caution in patients with a history of episodes of mania/hypomania. The drug should be discontinued if a manic state develops.

Angle-closure glaucoma
Pupil dilation, which occurs after taking many antidepressants, including Brintellix, can provoke an attack of closed-angle glaucoma in patients with an anatomically narrow anterior chamber angle who have not undergone peripheral iridectomy.

Bleeding

Rare cases of hemorrhagic disorders such as ecchymoses, purpura, gastrointestinal and gynecological bleeding have been reported during the use of serotonergic antidepressants (SSRIs, SNRIs).

The drug is recommended to be used with caution in patients taking anticoagulants and/or drugs that affect platelet function (for example, atypical antipsychotics, phenothiazines, most tricyclic antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid) (see section “Interaction with other drugs”), as well as in patients with a known tendency to bleeding/clotting disorders.

Hyponatremia

Rare cases of hyponatremia, possibly due to the syndrome of inappropriate antidiuretic hormone secretion, have been reported during the use of antidepressants with serotonergic effects (SSRIs, SNRIs).

Caution should be exercised when using vortioxetine in high-risk patients, such as elderly patients, patients with cirrhosis, or patients concomitantly receiving drugs that can cause hyponatremia.

If possible, Brintellix should be discontinued in patients with symptomatic hyponatremia and appropriate medical interventions should be implemented to correct their condition.

Elderly patients
Data on the use of Brintellix in elderly patients with a major depressive episode are limited. Therefore, caution should be exercised when treating patients ≥ 65 years of age with doses of vortioxetine above 10 mg once daily (see sections “Pharmacological properties” and “Side effects”).

Renal dysfunction
There are only limited data on the use of the drug in patients with severe renal failure. Therefore, caution should be exercised when treating these patients (see section “Pharmacological properties”).

Liver dysfunction
Vortioxetine has not been studied in patients with severe hepatic impairment, so the drug should be used with caution in such patients (see section “Pharmacological properties”).

Impact on the ability to drive vehicles and operate machinery

Brintellix has no or very little effect on the ability to drive a car or use machinery. However, patients should exercise caution when driving or operating hazardous machinery, especially when starting treatment with vortioxetine or when changing its dose.

Active ingredient

Vortioxetine

Composition

The active substance is vortioxetine hydrobromide 25.420 mg, which is equivalent to 20 mg of vortioxetine.

Excipients:
mannitol 91.58 mg,
microcrystalline cellulose 22.5 mg,

Pregnancy

Pregnancy
Data on the use of vortioxetine in pregnant women are limited. Animal studies have shown reproductive toxicity of vortioxetine (see section “Pharmacological properties”).

In newborns whose mothers receive serotonergic drugs in late pregnancy, the following symptoms may occur: respiratory distress, cyanosis, apnea, seizures, temperature instability, difficulty eating, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, increased neuro-reflex excitability, irritability, lethargic sleep, constant crying, somnolence and poor dream. These symptoms may be due to either withdrawal symptoms or excessive serotonergic activity. In most cases, these complications begin immediately or shortly (< 24 hours) after birth.

Evidence from epidemiological studies suggests that use of SSRIs during pregnancy, especially later in pregnancy, may increase the risk of developing persistent pulmonary hypertension of the newborn (PPHN). Although to date the possibility of a relationship between this condition and the use of vortioxetine has not been studied, taking into account its mechanism of action (increased serotonin concentrations), a possible risk cannot be excluded.

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

Breastfeeding
Available pharmacodynamic and toxicological data in animals have shown that vortioxetine and its metabolites are excreted in breast milk. It is likely that vortioxetine also passes into breast milk in humans (see section “Pharmacological properties”).

The risk to the baby during breastfeeding cannot be excluded.

The decision to discontinue breastfeeding or refrain from using Brintellix should be made based on an assessment of the relative benefits of breastfeeding for the child and the need for therapy for the mother.

Fertility
Fertility studies in male and female rats have shown that vortioxetine has no effect on fertility, sperm quality, or mating ability (see Pharmacological Properties).

Cases of human use of drugs belonging to the corresponding pharmacological class of antidepressants (SSRIs) have shown the presence of effects on sperm quality that are reversible. No effects on human fertility have been observed to date.

Contraindications

Hypersensitivity to the active substance or any component of the drug.
Concomitant use with non-selective monoamine oxidase inhibitors (MAOIs) or with selective MAO A inhibitors (see section “Interaction with other drugs”).
Children and adolescents under 18 years of age (safety and effectiveness have not been established).

Interaction

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

Possible influence of other drugs on the pharmacological action of vortioxetine
Irreversible non-selective MAO inhibitors
Due to the risk of serotonin syndrome, vortioxetine is contraindicated in combination with irreversible non-selective MAO inhibitors. Vortioxetine can be prescribed no earlier than 14 days after discontinuation of irreversible non-selective MAO inhibitors. Vortioxetine must be discontinued at least 14 days before starting the use of irreversible non-selective MAO inhibitors (see section “Contraindications”).

Reversible selective MAO A inhibitors (moclobemide)
The simultaneous use of vortioxetine with reversible selective MAO A inhibitors, such as moclobemide, is contraindicated (see section “Contraindications”). In case of proven need for simultaneous use, the added drug should be used in minimal doses and with careful clinical monitoring for the occurrence of serotonin syndrome (see section “Special Instructions”).

Reversible non-selective MAO inhibitors (linezolid)
Concomitant use of vortioxetine with a weak, reversible, non-selective MAO inhibitor, such as the antibiotic linezolid, is contraindicated (see section “Contraindications”). In case of proven need for simultaneous use, the added drug should be used in minimal doses with careful clinical monitoring for the occurrence of serotonin syndrome (see section “Special Instructions”).

Irreversible selective MAO B inhibitors (selegiline, rasagiline)
Although the risk of serotonin syndrome with concomitant use of vortioxetine and selective MAO B inhibitors is lower than with concomitant use of vortioxetine and selective MAO A inhibitors, the combined use of vortioxetine with irreversible MAO B inhibitors such as selegiline or rasagiline should be used with caution. In case of simultaneous use, the patient must be carefully monitored for the occurrence of serotonin syndrome (see section “Special Instructions”).

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

St. John’s wort
Concomitant use of antidepressants with a serotonergic effect with drugs containing St. John’s wort (Hypericum perforatum) may lead to an increased incidence of adverse reactions, including serotonin syndrome (see section “Special Instructions”).

Drugs that lower the seizure threshold
Antidepressants with serotonergic effects may lower the seizure threshold. Concomitant use with drugs that lower the seizure threshold (for example, antidepressants (TCAs, SSRIs, SNRIs), antipsychotics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion, tramadol) should be carried out with caution (see section “Special Instructions”).

ECT (electroconvulsive therapy)
There is currently no clinical experience with the concomitant use of vortioxetine and ECT, so caution should be exercised with such use.

CYP2D6 isoenzyme inhibitors
When vortioxetine 10 mg/day was administered concomitantly with bupropion (a strong CYP2D6 inhibitor) 150 mg twice daily for 14 days in healthy subjects, vortioxetine exposure (AUC) increased 2.3-fold. Adverse reactions were observed more frequently when bupropion was added to current vortioxetine therapy than when vortioxetine was added to current bupropion therapy. Depending on the individual patient’s response, when adding a strong inhibitor of the CYP2D6 isoenzyme (for example, bupropion, quinidine, fluoxetine, paroxetine) to the current therapy with vortioxetine, the possibility of reducing the dose of vortioxetine should be considered (see section “Dosage and Administration”).

Inhibitors of CYP3A4 and CYP2C9 isoenzymes
Adding vortioxetine 6 days after starting ketoconazole 400 mg/day (inhibitor of CYP3A4/5 and P-glycoprotein isoenzymes) or 6 days after starting fluconazole 200 mg/day (inhibitor of CYP2C9, CYP2C19 and CYP3A4/5 isoenzymes) in healthy subjects exposure (AUC) vortioxetine increased by 1.3 and 1.5 times, respectively. No dose adjustment is required.

Interactions in patients with weak activity of the CYP2D6 isoenzyme
Specific studies of the use of vortioxetine concomitantly with strong CYP3A4 inhibitors (such as itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, conivaptan and many HIV protease inhibitors) and CYP2C9 inhibitors (such as fluconazole and amiodarone) in patients with reduced CYP2D6 activity (see section Pharmacological Properties has not been evaluated, however, in these patients such use would be expected to result in greater exposure to vortioxetine than the moderate exposure described above. Taking a single dose of omeprazole 40 mg (CYP2C19 inhibitor) with repeated doses of vortioxetine did not change the pharmacokinetics of the latter in healthy subjects.

Cytochrome P450 inducers
When a single dose of vortioxetine 20 mg was administered 10 days after initiation of rifampicin 600 mg/day (a broad-spectrum CYP isoenzyme inducer) in healthy subjects, vortioxetine exposure (AUC) was reduced by 72%. Depending on the individual response of the patient, when adding a strong inducer of broad-spectrum cytochrome P450 isoenzymes (for example, rifampicin, carbamazepine, phenytoin) to the current therapy with vortioxetine, the possibility of adjusting the dose of vortioxetine should be considered (see section “Dosage and Administration”).

Alcohol
When single doses of vortioxetine (20 mg and 40 mg) and ethanol (0.6 g/kg) were co-administered to healthy subjects, there were no changes in the pharmacokinetics of vortioxetine or ethanol and no significant impairment in cognitive function compared to placebo. However, alcohol intake is not recommended during antidepressant therapy.

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

Possible influence of vortioxetine on the pharmacological action of other drugs
Anticoagulants and antiplatelet agents
There was no significant effect of vortioxetine compared with placebo on prothrombin parameters, international normalized ratio (INR), or plasma R-R-/S-warfarin ratio when multiple doses of vortioxetine were coadministered with fixed-dose warfarin in healthy subjects. There was also no significant inhibitory effect of vortioxetine on platelet aggregation and the pharmacokinetics of acetylsalicylic acid and salicylic acid compared to placebo when administered concomitantly with acetylsalicylic acid at a dose of 150 mg/day after multiple doses of vortioxetine in healthy subjects. However, as with the use of other serotonergic drugs, caution should be exercised when vortioxetine is used concomitantly with oral anticoagulants or antiplatelet agents due to the potential risk of bleeding caused by pharmacodynamic interactions (see section “Special Instructions”).

Cytochrome P450 substrates
In vitro studies have not revealed the ability of vortioxetine to inhibit or induce isoenzymes of the cytochrome P450 system (see section “Pharmacological properties”).

After multiple doses of vortioxetine in healthy subjects, no inhibitory effect was found on the activity of cytochrome P450 isoenzymes CYP2C19 (omeprazole, diazepam), CYP3A4/5 (ethinyl estradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (tolbutamide, S-warfarin), CYP1A2 (caffeine) or CYP2D6 (dextromethorphan).

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

Lithium, tryptophan
In healthy subjects, no clinically significant changes were observed with concomitant use of lithium and multiple doses of vortioxetine. However, due to the fact that cases of increased effects of serotonergic antidepressants have been described when used concomitantly with lithium or tryptophan, the use of vortioxetine in combination with these drugs should be used with caution.

Overdose

Currently, there is only limited experience with vortioxetine overdose.

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

Treatment: In case of overdose, it is necessary to monitor the patient and carry out symptomatic treatment. It is also recommended that follow-up medical care be carried out in specialized settings.

Manufacturer

H. Lundbeck A/O, Denmark