Instructions for Brintellix film-coated tablets 10 mg blister No. 28
Composition
active ingredient: vortioxetine;
1 film-coated tablet contains 5 mg or 10 mg of vortioxetine as vortioxetine hydrobromide;
excipients: mannitol (E 421), microcrystalline cellulose, hydroxypropylcellulose, sodium starch glycolate (type A), magnesium stearate, hypromellose, macrogol 400, titanium dioxide (E 171); 5 mg tablets: red iron oxide (E 172); 10 mg tablets: yellow iron oxide (E 172).
Dosage form
Film-coated tablets.
Main physicochemical properties:
5 mg tablets: pink, teardrop-shaped, film-coated tablets, with the symbols “TL” on one side and “5” on the other;
10 mg tablets: yellow, teardrop-shaped, film-coated tablets, debossed with “TL” on one side and “10” on the other.
Pharmacotherapeutic group
Antidepressants. ATX code N06A X26.
Pharmacological properties
Pharmacodynamics.
Mechanism of action
The mechanism of action of vortioxetine is believed to be related to its multimodal activity, which is a combination of two pharmacological mechanisms: direct modulation of receptor activity and inhibition of the serotonin (5-HT) transporter. Preclinical data indicate that vortioxetine is an antagonist of 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist of 5-HT1B receptors, an agonist of 5-HT1A receptors, and an inhibitor of the 5-HT transporter, resulting in modulation of neurotransmission in multiple systems, including serotonin, norepinephrine, dopamine, histamine, acetylcholine, GABA, and glutamate. This multimodal activity is believed to provide antidepressant and anxiolytic effects, as well as improvements in cognitive function, learning, and memory in preclinical studies of vortioxetine. In addition, preclinical studies indicate that vortioxetine does not cause sexual dysfunction. The precise contribution of each component of this mechanism to the observed pharmacodynamic profile remains unclear, and extrapolation of preclinical data requires special attention to the patient.
Two clinical positron emission tomography (PET) studies were conducted using 5-HT receptor ligands (11C-MADAM or 11C-DASB) to quantify 5-HT receptor uptake in the brain at different dose levels.
Serotonin transporter uptake was found to be approximately 50% at a daily dose of vortioxetine 5 mg, 65% at a daily dose of vortioxetine 10 mg, and over 80% at a daily dose of vortioxetine 20 mg.
Clinical efficacy and safety
The efficacy and safety of vortioxetine have been studied in a number of clinical trials involving over 6700 patients, of which over 3700 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 efficacy of vortioxetine in MDD in adult patients (including elderly patients). Efficacy of vortioxetine was demonstrated in at least the single-dose group in 9 of the 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 Rating Scale (HAM-D24). This was clinically confirmed by the number of patients who responded to treatment and achieved remission, as well as by improvement on the Clinical Global Impression-I (CGI-I). The efficacy of vortioxetine increased with increasing dose.
The efficacy of individual studies was confirmed by a meta-analysis (MMRM) of the mean changes in MADRS total score over 6/8 weeks of 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 a dose of 15 mg/day, statistically significant differences from placebo were achieved according to the meta-analysis, but the mean differences compared to placebo were -2.6 points. The efficacy of vortioxetine was also confirmed in the pooled analysis, in which the percentage of responders was 46% to 49% with vortioxetine compared to 34% with placebo (p < 0.01; NRI analysis).
In addition, vortioxetine in the dose range of 5–20 mg/day demonstrated efficacy on a broad spectrum of depressive symptoms (assessed by change in scores on all individual MADRS subscales).
The efficacy of vortioxetine at doses of 10 or 20 mg/day was also demonstrated in a 12-week, double-blind, variable-dose comparative study with agomelatine at doses of 25 or 50 mg/day in patients with BPD. Vortioxetine demonstrated a statistically significant advantage over agomelatine in the MADRS total score, which was also clinically meaningful in the number of patients who responded to therapy and achieved remission and improvement on the CGI-I scale.
The durability of the antidepressant effect with maintenance therapy was demonstrated in a relapse prevention study. Patients who were in remission after initial treatment with vortioxetine in a 12-week open-label study were randomized to vortioxetine 5 or 10 mg/day or placebo and were followed for relapse for at least 24 weeks (range 24 to 64 weeks) in a double-blind manner. Vortioxetine was superior to placebo (p = 0.004) on the primary endpoint of time to relapse of VDR, with a hazard ratio of 2; this means that the risk of relapse was 2-fold higher in the placebo group than in the vortioxetine group.
Elderly patients
In a double-blind, placebo-controlled, 8-week, fixed-dose study in elderly patients with depression (≥65 years, n = 452, 156 of whom received vortioxetine), vortioxetine 5 mg/day was superior to placebo in terms of the MADRS total score and HAM-D24. 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 high levels of anxiety symptoms
Antidepressant efficacy was also demonstrated in patients with severe depression (≥ 30 MADRS points) and in depressed patients with high levels of anxiety symptoms (≥ 20 HAM-A points) in short-term studies in adults (mean change 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 elderly patients, vortioxetine also showed efficacy in this patient group. The persistence of the antidepressant effect in this patient group was also demonstrated in a long-term relapse prevention study.
Effects of vortioxetine on the Digit Symbol Substitution Test (DSST), the University of California San Diego Scale (UPSA) for the quality of life (objective measures), and the Perceived Deficits Questionnaire (PDQ) and Cognitive and Physical Functioning Questionnaire (CPFQ) scores (subjective measures).
The efficacy of vortioxetine (5–20 mg/day) in patients with VDR was studied in two short-term placebo-controlled studies in adults and one in elderly patients.
Vortioxetine had a statistically significant effect on the DSST compared to placebo, with Δ = 1.75 (p = 0.019) to 4.26 (p < 0.0001) in the two studies in adults and Δ = 2.79 (p = 0.023) in the study in elderly patients. In a meta-analysis (ANCOVA, LOCF) of the mean change from baseline in the number of correct symbols on the DSST across 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 score, 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 capacity using the UPSA. Vortioxetine was statistically significantly different from placebo with results of 8 points for vortioxetine versus 5.1 points for placebo (p = 0.0003).
In one study, vortioxetine was superior to placebo on subjective measures measured by the PDQ, with scores of -14.6 for vortioxetine and -10.5 for placebo (p = 0.002). Vortioxetine did not differ from placebo on subjective measures measured by the CPFQ, with scores of -8.1 for vortioxetine versus -6.9 for placebo (p = 0.086).
Tolerability and safety
The safety and tolerability of vortioxetine at doses of 5–20 mg/day were evaluated in short- and long-term studies.
Information on undesirable side reactions is presented in the "Adverse reactions" section.
Vortioxetine did not increase the incidence of insomnia or somnolence compared to placebo.
In short-term and long-term placebo-controlled clinical trials, the potential for withdrawal symptoms following abrupt discontinuation of vortioxetine was consistently assessed. No clinically significant difference was found between vortioxetine and placebo in the frequency and nature of withdrawal symptoms after either short-term (6–12 weeks) or long-term (24–64 weeks) treatment.
The effect of vortioxetine on sexual function was further evaluated in an 8-week, double-blind, flexible-dose, comparative study (n = 424) with escitalopram in patients who had been receiving SSRIs (citalopram, paroxetine, or sertraline) for at least 6 weeks and had low levels of depressive symptoms (baseline CGI-S ≤ 3) and TESD caused by prior SSRI treatment. Vortioxetine 10–20 mg/day had a statistically significantly lower TESD than escitalopram 10–20 mg/day, as measured by the change in CSFQ-14 total score (2.2 points, p = 0.013) at week 8. The number of patients who responded to therapy was not significantly different in the vortioxetine group (162 (74.7%)) compared with the escitalopram group (137 (66.2%)) at week 8 (OR 1.5 p = 0.057). The antidepressant effect was maintained in both treatment groups.
In short- and long-term clinical studies, vortioxetine, like placebo, had no effect on body weight, heart rate, or blood pressure.
There were no clinically significant changes in liver and kidney function tests during clinical studies.
Vortioxetine did not have any clinically significant effects on ECG parameters, including QT, QTc, PR, and QRS intervals, in patients with major depressive disorder. In a thorough QTc study in healthy volunteers, no potential for QTc prolongation was observed at doses up to 40 mg/day.
Pediatric population
One randomized, double-blind, placebo-controlled, active comparator-controlled, fixed-dose, 8-week study was conducted in patients with ADHD aged 12 to 17 years. This study included a 4-week, blinded, placebo-controlled run-in period with a standardized psychosocial intervention (N = 777); only patients who were non-responders to the run-in period (N = 615) were eligible for randomization. Vortioxetine, at a dose of 10 mg/day or 20 mg/day, was not statistically superior to placebo on the Children's Depression Rating Scale-Revised (CDRS-R) total score. The active comparator (fluoxetine, 20 mg/day) was statistically significantly different from placebo on the CDRS-R total score. In general, the adverse reaction profile of vortioxetine in adolescents was similar to that observed in adults, with the exception of more frequent events related to abdominal pain and suicidal ideation in adolescents. Discontinuation of the study due to adverse events (mainly suicidal ideation, nausea and vomiting) was more common in patients treated with vortioxetine 20 mg/day (5.6%) compared to patients treated with vortioxetine 10 mg/day (2.7%), fluoxetine (3.3%) and placebo (1.3%). The most commonly reported adverse events in the vortioxetine-treated groups were nausea, vomiting and headache. Suicidal ideation and suicidal behavior were reported as adverse events during both the 4-week blinded run-in period (placebo, 13/777 [1.7%]) and the 8-week treatment period (vortioxetine, 10 mg daily, 2/147 [1.4%], vortioxetine, 20 mg daily, 6/161 [3.7%], fluoxetine, 6/153 [3.9%], placebo, 0/154 [0%]). Suicidal ideation and suicidal behavior as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) were similar across treatment groups.
The European Medicines Agency has waived its obligation to submit the results of studies with vortioxetine in the treatment of major depressive disorder in patients aged less than 7 years (see section 4.2).
The European Medicines Agency has deferred the obligation to submit the results of studies with vortioxetine in the treatment of major depressive disorder in children or adolescents aged 7 to 18 years (see section 4.2).
Pharmacokinetics.
Absorption
Vortioxetine is slowly but well absorbed after oral administration, with peak plasma concentrations occurring within 7–11 hours. After multiple doses of 5, 10, or 20 mg daily, mean Cmax values of 9–33 ng/mL were observed. Absolute bioavailability is 75%. No effect of food on pharmacokinetics was observed.
Distribution
The mean volume of distribution (Vss) is 2600 L, indicating extensive extravascular distribution.
Vortioxetine is highly bound to plasma proteins (98–99%) and binding is likely independent of vortioxetine plasma concentration.
Biotransformation
Vortioxetine is extensively metabolized in the liver, primarily by 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 have not revealed any inhibitory or inducing effects of vortioxetine 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 P-gp substrate and inhibitor. The major metabolite of vortioxetine is pharmacologically inactive.
Elimination
The mean elimination half-life and oral clearance are 66 h and 33 l/h, respectively. Approximately 2/3 of the inactive metabolite of vortioxetine is excreted in the urine and approximately 1/3 in the feces. Only a small amount of vortioxetine is excreted in the feces. Steady-state plasma concentrations are reached after approximately 2 weeks.
The pharmacokinetics are linear and independent of time over the dose range studied (2.5–60 mg/day). According to the half-life, the accumulation index is 5 to 6 based on AUC0-24 after multiple doses of 5 to 20 mg/day.
Elderly patients
In elderly healthy volunteers (aged ≥ 65 years, n=20), vortioxetine exposure was increased by 27% (Cmax and AUC) compared to young healthy control volunteers (aged ≤ 45 years) after multiple doses of 10 mg/day. The minimum effective dose of vortioxetine of 5 mg/day should always be used as the starting dose for patients aged ≥ 65 years (see Dosage and Administration). Caution should be exercised when prescribing vortioxetine to elderly patients at doses above 10 mg/day (see Precautions).
Kidney failure
Following a single dose of 10 mg vortioxetine, renal impairment (Cockroft-Gault mild, moderate or severe; n=8 per group) resulted in a small increase in exposure (up to 30%) compared to that in healthy control subjects. In patients with end-stage renal disease, only a small fraction of vortioxetine was lost during dialysis (AUC and Cmax 13% and 27% lower; n=8) following a single dose of 10 mg vortioxetine. No dose adjustment is required for patients with renal impairment (see sections 4.2 and 4.4).
Liver failure
Pharmacokinetics in subjects (N=6 in the severe hepatic impairment group and N=8 in the mild and moderate hepatic impairment group) with mild, moderate or severe hepatic impairment (Child-Pugh class A, B or C, respectively) were comparable to those in healthy subjects. Changes in AUC were less than 10% in subjects with mild or moderate hepatic impairment and 10% higher in subjects with severe hepatic impairment compared to healthy control subjects. Changes in Cmax were less than 25% in all groups compared to healthy control subjects. No dose adjustment is required for patients with hepatic impairment (see sections 4.2 and 4.4).
Poor CYP2D6 metabolizers
In CYP2D6 poor metabolizers, plasma concentrations of vortioxetine were approximately two-fold higher than in extensive metabolizers. In the presence of strong CYP3A4/2C9 inhibitors, the effect could potentially be greater.
In patients with extremely rapid metabolism of the CYP2D6 isoenzyme, plasma concentrations of vortioxetine at a dose of 10 mg/day were within the range of values obtained in extensive metabolizers after administration of 5 and 10 mg/day.
Dose adjustment may be necessary, as for all patients, depending on individual response.
Pediatric population
The pharmacokinetics of vortioxetine in pediatric patients with major depressive disorder following oral dosing of 5–20 mg once daily were characterized using population modeling analyses based on data from a pharmacokinetic study (in children 7–17 years of age) and an efficacy and safety study (in children 12–17 years of age). The pharmacokinetics of vortioxetine in pediatric patients were similar to those observed in adult patients.
Indication
Treatment of major depressive disorder in adults.
Contraindication
Hypersensitivity to the active substance or to any component of the drug.
Concomitant use with non-selective monoamine oxidase inhibitors (MAOIs) or selective MAO-A inhibitors.
Interaction with other medicinal products and other types of interactions
Vortioxetine is extensively metabolized in the liver, primarily by oxidation catalyzed by CYP2D6 and to a minor extent by CYP3A4/5 and CYP2C9.
Effect of other medicinal products on the action of vortioxetine
Irreversible non-selective MAO inhibitors
Due to the risk of serotonin syndrome, vortioxetine is contraindicated in any combination with irreversible non-selective MAOIs. Treatment with vortioxetine should not be initiated until at least 14 days after discontinuation of treatment with irreversible non-selective MAOIs. Vortioxetine should be discontinued at least 14 days before initiation of treatment with irreversible non-selective MAOIs.
Reversible selective MAO-A inhibitor (moclobemide)
The combination of vortioxetine with a reversible selective MAO-A inhibitor such as moclobemide is contraindicated. If the combination is necessary, the drug should be added, starting at the lowest dosage and with close clinical monitoring for serotonin syndrome.
Reversible non-selective MAO inhibitor (linezolid)
The combination of vortioxetine with a weak reversible and nonselective MAOI, such as the antibiotic linezolid, is contraindicated. If the combination is necessary, the drug should be added starting at the lowest dosage and with close clinical monitoring for serotonin syndrome.
Despite the lower expected risk of serotonin syndrome than with MAO-A inhibitors, the combination of vortioxetine with irreversible MAO-B inhibitors such as selegiline or rasagiline should be undertaken with caution. Close monitoring for serotonin syndrome is necessary during concomitant use.
Serotonergic drugs
Concomitant administration with serotonergic drugs (e.g. opioids (including tramadol) and triptans (including sumatriptan)) may lead to serotonin syndrome.
Hypericum
Concomitant use of serotonergic antidepressants and herbal remedies containing St. John's wort may lead to an increased incidence of adverse reactions, including serotonin syndrome.
Medications that lower the seizure threshold
Serotonergic antidepressants may lower the seizure threshold. Caution is advised when co-administering other medicinal products that may lower the seizure threshold (such as antidepressants (TCAs, SSRIs, SNRIs), neuroleptics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion and tramadol).
ECT (electroconvulsive therapy)
There is no clinical experience with the concomitant use of vortioxetine with ECT, therefore caution is advisable.
CYP2D6 inhibitors
When co-administered with 150 mg bupropion (a strong CYP2D6 inhibitor) twice daily for 14 days in healthy volunteers, vortioxetine exposure increased 2.3-fold for AUC. Co-administration was more likely to result in an increased incidence of adverse events when bupropion was added to vortioxetine than when vortioxetine was added to bupropion. Depending on individual patient sensitivity, lower doses of vortioxetine may be considered when strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to therapy.
CYP3A4, CYP2C9 and CYP2C19 inhibitors
When vortioxetine was co-administered with ketoconazole 400 mg daily (CYP3A4/5 and P-glycoprotein inhibitor) or fluconazole 200 mg daily (CYP2C9, CYP2C19 and CYP3A4/5 inhibitor) for 6 days in healthy volunteers, a 1.3- and 1.5-fold increase in vortioxetine AUC was observed, respectively. No dose adjustment is required.
The effect of a single dose of 40 mg omeprazole (a CYP2C19 inhibitor) on the pharmacokinetics of chronic vortioxetine in healthy volunteers was not observed.
Interaction with CYP2D6 poor metabolizers
The concomitant use of 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 CYP2D6 poor metabolisers has not been specifically studied, but is expected to result in a more pronounced increase in vortioxetine exposure in these patients compared to the modest effect described above. Depending on the individual patient response, a lower dose of vortioxetine may be considered if a strong CYP3A4 or CYP2C9 inhibitor is co-administered with CYP2D6 poor metabolisers.
Cytochrome P450 inducers
A single dose of 20 mg vortioxetine administered 10 days after initiation of rifampicin 600 mg daily (a broad CYP inducer) in healthy volunteers resulted in a 72% decrease in vortioxetine AUC. Depending on individual patient response, dose adjustment may be necessary when a broad cytochrome P450 inducer (e.g. rifampicin, carbamazepine, phenytoin) is added to vortioxetine treatment.
Alcohol
No effect on the pharmacokinetics of vortioxetine or ethanol, or significant impairment of cognitive function compared to placebo, was observed after administration of vortioxetine at doses of 20 mg or 40 mg with a single administration of ethanol 0.6 g/kg in healthy volunteers. However, as with other CNS depressants, the combination of vortioxetine and alcohol is not recommended.
Acetylsalicylic acid
The effect of repeated administration of acetylsalicylic acid at a dose of 150 mg per day on the pharmacokinetics of vortioxetine in healthy volunteers was not observed.
Effect of vortioxetine on the action of other drugs
Anticoagulants and antiplatelet agents
No significant effect on plasma international normalized ratio, prothrombin time, or R-/S-warfarin was observed compared to placebo when vortioxetine was co-administered with fixed-dose warfarin in healthy volunteers. In addition, no significant inhibitory effect on platelet aggregation was observed compared to placebo when aspirin 150 mg daily was co-administered after vortioxetine in healthy volunteers. However, caution should be exercised when vortioxetine is used in combination with oral anticoagulants or antiplatelet agents due to the potential for increased bleeding risk due to pharmacodynamic interactions.
Cytochrome P450 substrates
In vitro, vortioxetine did not show any relevant potential for inhibition or induction of cytochrome P450 isozymes.
No inhibitory effect of vortioxetine on cytochrome P450 isoenzymes CYP2C19 (omeprazole, diazepam), CYP3A4/5 (ethinyl estradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (tolbutamide, S-warfarin), CYP1A2 (caffeine), or CYP2D6 (dextromethorphan) was detected in healthy volunteers.
No significant effect on sex hormone levels compared to placebo was observed after concomitant use of vortioxetine with a combined oral contraceptive (ethinyl estradiol 30 mcg/levonorgestrel 150 mcg).
Lithium, tryptophan
No clinically significant changes were observed after concomitant administration of stable concentrations of lithium with vortioxetine in healthy volunteers. However, there have been reports of enhanced effects when serotonergic antidepressants are used together with lithium or tryptophan, therefore, concomitant administration of vortioxetine with these drugs should be undertaken with caution.
Interference with the results of a urine drug test
False-positive results of urine enzyme immunoassays for methadone have been reported in patients taking vortioxetine. Caution should be exercised when interpreting positive results of urine drug tests and confirmation by alternative analytical methods (e.g., chromatographic methods) should be considered.
Application features
Use in the pediatric patient population
Vortioxetine is not recommended for the treatment of depression in pediatric patients aged 7 to 11 years as safety and efficacy have not been established in this age group. Brintellix should not be used in the treatment of major depressive disorder in adolescents aged 12 to 17 years as efficacy has not been demonstrated (see section 5.1). The adverse reaction profile of vortioxetine in adolescents was generally similar to that observed in adults, with the exception of more frequent events related to abdominal pain and suicidal ideation in adolescents (see sections 4.8 and 5.1). In clinical trials, suicidal behaviour (suicide attempt and suicidal ideation) and hostility (predominantly aggression, oppositional behaviour, anger) were observed more frequently in children treated with antidepressants than in patients treated with placebo.
Suicide/suicidal thoughts
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide (suicide-related events). This risk persists until significant remission is achieved. As improvement may not occur within the first few weeks or more of treatment, patients should be closely monitored until improvement occurs. It is general clinical experience that the risk of suicide may be increased in the early stages of recovery.
Patients with a history of suicide-related events or who exhibit significant signs of suicidal ideation prior to initiation of treatment are known to be at greater risk of suicidal thoughts or suicide attempts and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour compared to placebo in patients aged <25 years.
Close monitoring of patients, and in particular those at high risk, should accompany treatment, especially at the beginning of therapy and after dose changes. Patients (and their caregivers) should be warned about the need to monitor for any clinical worsening, suicidal behavior or thoughts, and unusual changes in behavior, and to seek medical advice immediately if these symptoms present.
Convulsions
Seizures are a potential risk with antidepressants. Therefore, vortioxetine should be initiated with caution in patients with a history of seizures or in patients with unstable epilepsy. Treatment should be discontinued in any patient if seizures develop or increase in frequency.
Serotonin syndrome or neuroleptic malignant syndrome
Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS), potentially life-threatening conditions, may develop during treatment with vortioxetine. The risk of SS and NMS is increased with concomitant use of serotonergic agents (including opioids and triptans), agents that affect serotonin metabolism (including MAO inhibitors), antipsychotics, and other dopamine antagonists. Patients should be monitored closely for symptoms of SS or NMS.
Symptoms of SS include mental status changes (such as agitation, hallucinations, and coma), autonomic instability (such as tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (such as hyperreflexia, incoordination), and/or gastrointestinal symptoms (such as nausea, vomiting, and diarrhea). If such signs occur, vortioxetine should be discontinued immediately and symptomatic treatment initiated.
Mania/hypomania
Vortioxetine should be administered with caution to patients with a history of mania/hypomania and discontinued if a manic phase develops.
Aggression/agitation
Patients treated with antidepressants, including vortioxetine, may also experience feelings of aggression, anger, agitation, and irritability. Close monitoring of the patient and the disease is recommended. Patients (and their caregivers) should be advised to seek medical advice if aggressive/aggressive behavior develops or worsens.
As with any serotonergic antidepressant, including vortioxetine, abnormal bleeding such as bruising, purpura and other bleeding, including gastrointestinal or gynaecological bleeding, may occur. SSRIs/SNRIs may increase the risk of postpartum haemorrhage, and this risk may be potentially associated with vortioxetine (see section 4.6). Caution is advised in patients taking anticoagulants and/or medicinal products that affect platelet function (e.g. atypical antipsychotics and phenothiazines, most TCAs, non-steroidal anti-inflammatory drugs, acetylsalicylic acid) and in patients with a known bleeding tendency or coagulation disorders.
Hyponatremia
Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion, has been reported rarely with SSRIs and SNRIs. Caution should be exercised in patients at risk of hyponatraemia, such as the elderly, patients with cirrhosis, or those receiving concomitant medications known to cause hyponatraemia. In patients with symptomatic hyponatraemia, vortioxetine should be discontinued and appropriate medical intervention initiated.
Glaucoma
Mydriasis has been reported in association with the use of antidepressants, including vortioxetine. This mydriatic effect may potentiate the narrowing of the angle of the eye, leading to increased intraocular pressure and angle-closure glaucoma. Caution is advised when prescribing vortioxetine to patients with elevated intraocular pressure or those at risk for 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 over 65 years of age with doses exceeding 10 mg vortioxetine once daily (see sections 4.2 and 4.8).
Kidney or liver failure
Given that patients with renal or hepatic impairment are vulnerable, and given that data on the use of Brintellix in these subgroups are limited, caution should be exercised when treating patients with renal or hepatic impairment (see sections 4.2 and 5.2).
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per film-coated tablet, i.e. essentially 'sodium-free'.
Use during pregnancy or breastfeeding
Pregnancy
Experience with the use of vortioxetine in pregnant women is limited.
Animal studies have shown reproductive toxicity.
Following administration of serotonergic drugs to women in late pregnancy, the following symptoms may occur in the neonate: respiratory distress, cyanosis, dyspnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, nervousness, irritability, lethargy, constant crying, drowsiness, and difficulty sleeping. These symptoms may be related to withdrawal effects or excessive serotonergic activity. In most cases, these complications begin immediately or shortly (<24 hours) after delivery.
Epidemiological data have shown that the use of SSRIs during pregnancy, especially in late pregnancy, may increase the risk of persistent pulmonary hypertension of the newborn (PPHN). Although the association of PPHN with vortioxetine treatment has not been studied, this potential risk cannot be excluded given the mechanism of action (increased serotonin concentrations).
Brintellix should be used when the expected benefit to the mother outweighs the potential risk to the fetus.
Observational data suggest an increased risk (less than 2-fold) of postpartum hemorrhage after use of SSRIs or SNRIs within the month before delivery. Although no studies have examined the association between vortioxetine treatment and postpartum hemorrhage, the potential risk exists,
