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

Active ingredient

Composition

How to take, the dosage

Dosing regimen
The initial and recommended dose of Brintellix in adult patients under 65 years of age is 10 mg once daily. Depending on individual patient response, the daily dose may be increased to a maximum dose of 20 mg vortioxetine once daily or reduced to a minimum dose of 5 mg vortioxetine once daily.

After complete resolution of depression symptoms, it is recommended that treatment be continued for at least 6 months to consolidate the antidepressant effect.

Discontinuation of treatment
Patients treated with Brintellix can discontinue it immediately without the need for gradual dose reduction (see section on Pharmacological properties).

Particular patient groups
Elderly patients
In patients ≥65 years of age, the lowest effective dose of Brintellix 5 mg once daily should always be used as the starting dose. Caution should be exercised when treating patients ≥65 years of age with doses above 10 mg vortioxetine once daily, as data on the use of the drug in this group of patients are limited (see “Cautionary Note”).

Cytochrome P450 inhibitors
Depending on the patient’s individual response, a dose reduction of Brintellix may be required if therapy with strong CYP2D6 isoenzyme inhibitors (e.g., bupropion, quinidine, fluoxetine, paroxetine) is initiated (see “Interaction with other medicinal products” section).

Cytochrome P450 inducers
Depending on the patient’s individual reaction, Brintellix dose adjustment may be required if therapy with broad spectrum cytochrome P450 inducers (e.g., rifampicin, carbamazepine, phenytoin) is joined (see section “Interaction with other medicinal products”).

Children and adolescents (under 18 years)
Safety and efficacy of Brintellix in children and adolescents under 18 years of age has not been established. There are no data on this group of patients (see section “Cautions”).

Method of administration
Brintellix is intended for oral administration. The film-coated tablets can be taken regardless of meals.

Interaction

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

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

Reversible selective MAOA inhibitors (moclobemide)
Concomitant use of vortioxetine with reversible selective MAOA inhibitors, such as moclobemide, is contraindicated (see section “Contraindications”). If concomitant use is proven to be necessary, the concomitant drug should be used in minimal doses and with careful clinical observation for serotonin syndrome (see section “Special Precautions”).

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”). If concomitant use is proven to be necessary, the concomitant drug should be used in minimal doses with careful clinical monitoring for serotonin syndrome (see section “Special Precautions”).

Independent 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 performed with caution. In case of concomitant use, the patient should be closely monitored for serotonin syndrome (see section “Special Precautions”).

Serotonergic drugs
Simultaneous use of vortioxetine and other drugs with serotonergic effects (e.g., tramadol, sumatriptan and other triptans) may lead to serotonin syndrome (see section “Special Precautions”).

St. John’s Wort
Simultaneous use of antidepressants with serotonergic effects with preparations containing Hypericum perforatum may lead to an increased incidence of adverse reactions, including serotonin syndrome (see section “Special Precautions”).

Drugs that decrease the threshold of seizure readiness
Antidepressants with serotonergic effect may decrease the threshold of seizure readiness. Concomitant use with drugs that lower the seizure threshold (e.g., antidepressants (TCAs, SSRIs, SSRIsN), neuroleptics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion, tramadol) should be used with caution (see section “Special indications”).

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

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

Inhibitors of CYP3A4 and CYP2C9 isoenzymes
In 6 days after treatment with vortioxetine at a dose of 400 mg/day (CYP3A4/5 and P-glycoprotein isoenzyme inhibitor) or 6 days after initiation of fluconazole at a dose of 200 mg/day (CYP2C9, CYP2C19 and CYP3A4/5 isoenzyme inhibitor) vortioxetine exposure (AUC) was increased by 1.3 and 1.5 times respectively in healthy subjects. No dose adjustment is required.

Interactions in patients with weak CYP2D6 isoenzyme activity
Specific studies of vortioxetine concomitantly with strong CYP3A4 isoenzyme inhibitors (such as itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, conivaptan and many HIV protease inhibitors) and CYP2C9 isoenzyme inhibitors (such as fluconazole and amiodarone) in patients with decreased CYP2D6 isoenzyme activity (see Pharmacological properties” section) has not been performed, however, it can be expected that in these patients such use will result in a more pronounced exposure to vortioxetine compared to the moderate effects described above. A single dose of omeprazole 40 mg (a CYP2C19 isoenzyme inhibitor) against repeated doses of vortioxetine did not alter its pharmacokinetics in healthy subjects.

Cytochrome P450 inducers
When a single dose of vortioxetine 20 mg was taken 10 days after starting use of rifampicin at a dose of 600 mg/day (CYP broad spectrum isoenzyme inducer) by healthy subjects, the exposure (AUC) of vortioxetine was reduced by 72%. Depending on the patient’s individual response, if a strong broad-spectrum cytochrome P450 isoenzyme inducer (e.g., rifampicin, carbamazepine, phenytoin) is added to current vortioxetine therapy, vortioxetine dose adjustment should be considered (see section “Dosage and administration”).

Alcohol
No changes in the pharmacokinetics of vortioxetine or ethanol or significant cognitive impairment compared to placebo were observed in healthy subjects when single doses of vortioxetine (20 mg and 40 mg) and ethanol (0.6 g/kg) were taken simultaneously. However, alcohol intake is not recommended during antidepressant therapy.

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

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

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

. No inhibitory effect of vortioxetine on the activity of the CYP2C19 cytochrome P450 system isoenzymes (omeprazole, diazepam), CYP3A4/5 (ethinylestradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (tolbutamide, S-warfarin), CYP1A2 (caffeine) or CYP2D6 (dextromethorphan).

Pharmacodynamic interactions were also not observed. No significant cognitive impairment was found when vortioxetine was used in combination with a single dose of diazepam 10 mg compared to placebo. There was no significant effect of vortioxetine compared to placebo on sex hormone levels after use with the combined oral contraceptive (ethinylestradiol 30 mcg + levonorgestrel 150 mcg).

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

Special Instructions

Use in children and adolescents under 18 years of age

Brintellix is not recommended for therapy of depression in patients under 18 years of age because the safety and effectiveness of vortioxetine in this age group has not been established (see section “Dosage and administration”).

In clinical studies, children and adolescents who received other antidepressants were more likely to have suicidal behavior (suicide attempts and suicidal ideation) and hostility (with a predominance of aggressive behavior, confrontational tendencies and irritation) compared to those who received placebo.

Suicidal/suicidal thoughts or clinical deterioration

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

This risk persists until significant remission occurs. Because improvement may not be seen during the first few weeks of therapy or even longer, patients should be kept under constant observation until their condition improves.

Common clinical practice shows that in the early stages of recovery, there may be an increased risk of suicide.

Patients with a history of suicidal behavior or significant suicidal ideation prior to treatment are at greater risk for suicidal ideation or attempted suicide, so they must be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants involving adult patients with psychiatric disorders found an increased risk of suicidal behavior when using antidepressants in patients younger than 25 years compared to placebo.

Patients should be closely monitored, particularly those who are found to be at high suicidal risk, especially at the start of treatment or when the dose of medication is changed. Patients (and their caregivers) should be warned to watch for signs of any clinical deterioration, suicidal behavior and suicidal ideation, and unusual behavioral changes, and to seek immediate medical attention if these symptoms occur.

Seizures

There is a possible risk of 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 “Interaction with other medicinal products”). If seizures occur or their frequency increases, treatment with vortioxetine should be discontinued.

Serotonin syndrome or malignant neuroleptic syndrome

Serotonin syndrome (SS) or malignant neuroleptic syndrome (MNS) are potentially life-threatening conditions and can occur with Brintellix.

The risk of SS or MNS is increased when co-administered with serotonergic drugs (including triptans), drugs that affect serotonin metabolism (including IMAO), antipsychotics or other dopamine antagonists. Patients should be monitored for objective and subjective symptoms of SS and MNS (see Contraindications and Interactions with Other Drugs).

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

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

Closed angle glaucoma
Dilation of the pupils following administration of many antidepressants, including Brintellix, may provoke an attack of closed angle glaucoma in patients with an anatomically narrow anterior chamber angle who have not had a peripheral iridectomy.

Bleeding

In the background of serotonergic antidepressants (SSRIs, SSRIs), rare cases of hemorrhagic disorders such as ecchymoses, purpura, gastrointestinal and gynecological bleeding have been reported.

The drug is recommended with caution in patients taking anticoagulants and/or drugs affecting platelet function (e.g., atypical antipsychotics, phenothiazines, most tricyclic antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid) (see “Interaction with other drugs”). See section “Interaction with other medicinal products”), and in patients with a known tendency to bleeding/coagulability disorders.

Hyponatremia

A rare cases of hyponatremia have been reported with serotonergic antidepressants (SSRIs, SSRIs), probably due to inadequate antidiuretic hormone secretion syndrome.

Warning caution should be exercised when using vortioxetine in high-risk patients, such as elderly patients, patients with cirrhosis of the liver, or patients receiving concurrent therapy with drugs that may cause hyponatremia.

Brintellix should be discontinued if possible in patients with symptomatic hyponatremia and appropriate medical interventions should be made to correct their condition.

Elderly patients
Data on the use of Brintellix in elderly patients with 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 Pharmacological properties and side effects).

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

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

Brintellix has no or very little effect on the ability to drive or operate machinery. However, patients should exercise caution when driving or operating dangerous machinery especially at the beginning of treatment with vortioxetine or when changing its dose.

Contraindications

Overdose

There is currently only limited experience with vortioxetine overdose.

Symptoms: Oral administration of 40 to 75 mg vortioxetine has resulted in the following adverse reactions: nausea, postural dizziness, diarrhea, abdominal discomfort, generalized itching, drowsiness and hot flashes.

Treatment: In case of overdose, patient observation and symptomatic treatment should be established. Follow-up medical observation in specialized settings is also recommended.

Pregnancy use

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 late in pregnancy may experience the following symptoms: Respiratory distress, cyanosis, apnea, seizures, temperature instability, difficulty eating, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, increased neuroreflexivity, irritability, lethargic sleep, constant crying, sleepiness, and poor sleep. These symptoms may be related to both withdrawal syndrome and excess serotoninergic activity. In most cases, such complications begin immediately or shortly (< 24 hours) after birth.

The data from epidemiological studies suggest that SSRI use during pregnancy, particularly in the late term, may increase the risk of sustained pulmonary hypertension (PPHN) in the newborn. Although to date the possibility of a relationship between this condition and vortioxetine use has not been studied, given its mechanism of action (increased serotonin concentration) a possible risk cannot be ruled out.

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

Breastfeeding
Available pharmacodynamic and toxicological data in animals have shown that vortioxetine and its metabolites penetrate into breast milk. It is likely that vortioxetine also penetrates into breast milk in humans (see Pharmacological properties).

The risk to the baby during breastfeeding cannot be ruled out.

The decision to discontinue breastfeeding or to abstain from Brintellix should be based on an assessment of the relative benefit of breastfeeding to the baby and the need for therapy for the mother.

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

In human cases, medications in the relevant pharmacological class of antidepressants (SSRIs) have been shown to have effects on semen quality that are reversible. No effect on human fertility has been observed to date.