Arivox

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARIVOX

Composition:

active substance: vortioxetine;

1 film-coated tablet contains vortioxetine 10 mg (as vortioxetine hydrobromide 12.71 mg);

excipients: mannitol, microcrystalline cellulose, sodium starch glycolate (type A), hydroxypropylcellulose, magnesium stearate (vegetable);

coating of the tablet: hypromellose, titanium dioxide (E 171), polyethylene glycol 400, iron (III) hydroxide oxide (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: yellow, oval, film-coated tablets, engraved with "10" on one side and plain on the other side.

Pharmacotherapeutic group. Antidepressants. ATC code N06AX26.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

The mechanism of action of vortioxetine is believed to be related to its multimodal activity, which combines two pharmacological mechanisms: direct modulation of receptor activity and inhibition of the serotonin (5-HT) transporter. Preclinical data indicate that vortioxetine is an antagonist at 5-HT3, 5-HT7, and 5-HT1D receptors, a partial agonist at 5-HT1B receptors, an agonist at 5-HT1A receptors, and an inhibitor of the 5-HT transporter, thereby modulating neurotransmission in several systems, including serotonin, norepinephrine, dopamine, histamine, acetylcholine, GABA, and glutamate. This multimodal activity is believed to underlie the antidepressant and anxiolytic effects, as well as improvements in cognitive function, learning, and memory observed in preclinical studies of vortioxetine. Furthermore, preclinical studies suggest that vortioxetine does not cause sexual dysfunction. The precise contribution of each component of this mechanism to the observed pharmacodynamic profile remains unclear; therefore, particular caution is required when extrapolating preclinical data directly to patients.

Two clinical positron emission tomography (PET) studies using 5-HT receptor ligands (11C-MADAM or 11C-DASB) were conducted to quantitatively assess 5-HT transporter occupancy in the brain at various dose levels.

It was established that serotonin transporter occupancy was approximately 50% at a daily dose of vortioxetine 5 mg, 65% at a daily dose of 10 mg, and over 80% at a daily dose of 20 mg.

Clinical Efficacy and Safety

The efficacy and safety of vortioxetine were evaluated in a series of clinical trials involving over 6,700 patients, of whom more than 3,700 participated in short-term (≤12 weeks) studies in major depressive disorder (MDD). Twelve double-blind, placebo-controlled, fixed-dose 6- to 8-week trials were conducted to determine the short-term efficacy of vortioxetine in adult patients with MDD (including elderly patients). Efficacy of vortioxetine was demonstrated in at least one dose group in 9 out of 12 trials, showing a difference 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 who responded to therapy and achieved remission, as well as improvement on the Clinical Global Impression-Improvement scale (CGI-I). The efficacy of vortioxetine increased with dose escalation.

The efficacy of individual trials was confirmed by a meta-analysis (MMRM) of mean changes in total MADRS score over 6–8 weeks in short-term, placebo-controlled trials in adults. According to the meta-analysis results, 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 difference compared to placebo was -2.6 points. Efficacy of vortioxetine is further supported by a pooled analysis, in which the responder rate ranged from 46% to 49% with vortioxetine compared to 34% with placebo (p < 0.01; NRI analysis).

Furthermore, vortioxetine in the dose range of 5–20 mg/day demonstrated efficacy across a broad spectrum of depressive symptoms (assessed by changes in 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, flexible-dose comparative trial with agomelatine at doses of 25 or 50 mg/day in patients with MDD. Vortioxetine showed statistically significant superiority over agomelatine in total MADRS score, which was clinically meaningful, as well as in the number of patients who responded to therapy, achieved remission, and improved on the CGI-I scale.

Maintenance Therapy

The durability of the antidepressant effect during maintenance therapy was demonstrated in a relapse prevention study. Patients who were in remission after initial treatment with vortioxetine during a 12-week open-label study were randomized to receive either vortioxetine 5 or 10 mg/day or placebo and were observed for relapse during a double-blind phase lasting at least 24 weeks (ranging from 24 to 64 weeks). Vortioxetine was superior to placebo (p = 0.004) on the primary endpoint—time to relapse of MDD—with a hazard ratio of 2; this means that the risk of relapse was twice as high in the placebo group compared to the vortioxetine group.

Elderly Patients

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

Patients with Severe Depression or High Levels of Anxiety Symptoms

Antidepressant efficacy was also demonstrated in patients with severe depression (≥30 points on MADRS) and in depressed patients with high levels of anxiety symptoms (≥20 points on HAM-A) in short-term trials involving 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 involving elderly patients, vortioxetine demonstrated efficacy in this patient group. The durability of the antidepressant effect in this patient category was also demonstrated in a long-term relapse prevention study.

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

The efficacy of vortioxetine (at doses of 5–20 mg/day) in patients with MDD was evaluated in two short-term, placebo-controlled trials in adults and one trial in elderly patients.

Vortioxetine showed statistically significant improvement on the DSST compared to placebo, with Δ = 1.75 (p = 0.019) to 4.26 (p < 0.0001) in two trials in adults and Δ = 2.79 (p = 0.023) in the trial in elderly patients. In a meta-analysis (ANCOVA, LOCF) of mean change in the number of correct DSST symbols compared to baseline across all three trials, vortioxetine differed significantly 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 trials showed that vortioxetine differed from placebo (p < 0.05) with a standardized effect size of 0.24.

In one trial, the effect of vortioxetine on functional capacity was assessed using the UPSA. Vortioxetine differed significantly from placebo with scores of 8 points for vortioxetine versus 5.1 points for placebo (p = 0.0003).

In one trial, vortioxetine was superior to placebo on subjective measures assessed using 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 assessed using 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 per day were evaluated in short- and long-term studies.

Information on adverse reactions is provided in the section "Adverse Reactions."

Vortioxetine did not increase the frequency of insomnia or somnolence compared to placebo.

Possible withdrawal symptoms after abrupt discontinuation of vortioxetine were systematically assessed in both short- and long-term placebo-controlled clinical trials. No clinically significant differences between vortioxetine and placebo were observed in the frequency or nature of withdrawal symptoms, either after short-term (6–12 weeks) or long-term (24–64 weeks) treatment periods.

The incidence of spontaneously reported adverse reactions related to sexual dysfunction was low and similar to placebo in both short- and long-term vortioxetine trials. In studies using the Arizona Sexual Experience Scale (ASEX), the incidence of treatment-emergent sexual dysfunction (TESD) and the total ASEX score did not differ clinically significantly from placebo when vortioxetine was administered at doses of 5–15 mg/day. With vortioxetine at a dose of 20 mg/day, an increased incidence of sexual dysfunction was observed compared to placebo (difference in incidence 14.2%, 95% CI (1.4; 27)).

The effect of vortioxetine on sexual function was further evaluated in an 8-week, double-blind, flexible-dose comparative trial (n = 424) with escitalopram in patients who had received SSRIs (citalopram, paroxetine, or sertraline) for at least 6 weeks and had low levels of depressive symptoms (baseline CGI-S ≤ 3) and TESD due to prior SSRI treatment. Vortioxetine at doses of 10–20 mg/day showed a statistically significantly lower rate of TESD compared to escitalopram at doses of 10–20 mg/day, as measured by change in total CSFQ-14 score (2.2 points, p = 0.013) at week 8. The number of patients who responded to therapy did not differ significantly between the vortioxetine group (162 (74.7%)) and the escitalopram group (137 (66.2%)) at week 8 (OR 1.5, p = 0.057). Antidepressant effect was maintained in both treatment groups.

In clinical short- and long-term trials, vortioxetine, similar to placebo, did not affect body weight, heart rate, or blood pressure.

Clinically significant changes in liver and kidney function parameters were not observed during clinical trials.

Vortioxetine did not show any clinically significant effect 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 interval prolongation was observed at doses up to 40 mg per day.

Pediatric Population

Clinical trials in pediatric patients have not been conducted; therefore, the safety and efficacy of vortioxetine in patients under 18 years of age have not been established.

Pharmacokinetics

Absorption

Vortioxetine is slowly but well absorbed after oral administration, with peak plasma concentrations reached within 7–11 hours. After repeated administration of 5, 10, or 20 mg/day, mean Cmax values of 9–33 ng/mL were observed. Absolute bioavailability is 75%. No food effect on pharmacokinetics was observed.

Distribution

The mean volume of distribution (Vss) is 2,600 L, indicating extensive extravascular distribution.

Vortioxetine is highly bound to plasma proteins (98–99%), and binding is likely independent of vortioxetine plasma concentration.

Biological Transformation

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

In drug interaction studies, no inhibitory or inductive effect of vortioxetine on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 isoenzymes was observed (see "Interaction with Other Medicinal Products and Other Forms of Interaction"). Vortioxetine is a weak P-gp substrate and inhibitor. The main metabolite of vortioxetine is pharmacologically inactive.

Elimination

The mean elimination half-life and oral clearance are 66 hours and 33 L/h, respectively. Approximately two-thirds of the inactive metabolite of vortioxetine is excreted in urine and about one-third in feces. Only a negligible amount of vortioxetine is excreted in feces. Steady-state plasma concentration is reached after approximately 2 weeks.

Linearity / Non-linearity

Pharmacokinetics are linear and time-independent within the studied dose range (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 healthy elderly volunteers (age ≥ 65 years, n = 20), exposure to vortioxetine increased by 27% (Cmax and AUC) compared to young healthy volunteers in the control group (age ≤ 45 years) after multiple doses of 10 mg/day. The minimum effective dose of vortioxetine, 5 mg/day, should always be used as the starting dose in patients aged ≥65 years (see "Dosage and Administration"). Vortioxetine should be prescribed with caution at doses above 10 mg/day in elderly patients (see "Special Warnings and Precautions for Use").

Renal Impairment

After a single 10 mg dose, renal impairment (mild, moderate, or severe, as defined by the Cockcroft–Gault formula; n = 8 per group) resulted in a slight increase in exposure (up to 30%) compared to healthy control volunteers. In patients with end-stage renal disease, only a small fraction of vortioxetine was lost during dialysis (AUC and Cmax were 13% and 27% lower, respectively; n = 8) after a single 10 mg dose. Dose adjustment is not required in patients with impaired renal function (see "Dosage and Administration" and "Special Warnings and Precautions for Use").

Hepatic Impairment

Pharmacokinetics in individuals with mild, moderate, or severe hepatic impairment (Child–Pugh classes A, B, or C, respectively; N = 6 in the severe group and N = 8 in the mild/moderate group) were comparable to those in healthy volunteers. Changes in AUC were less than 10% in individuals with mild or moderate hepatic impairment and 10% higher in those with severe hepatic impairment compared to the control group of healthy volunteers. Changes in Cmax were less than 25% in all groups compared to the control group. Dose adjustment is not required in patients with impaired liver function (see "Dosage and Administration" and "Special Warnings and Precautions for Use").

Poor CYP2D6 Metabolizers

In poor CYP2D6 metabolizers, plasma concentrations of vortioxetine were approximately twice as high as in extensive metabolizers. The effect may potentially be higher in the presence of strong CYP3A4/2C9 inhibitors.

In patients with ultra-rapid metabolism of the CYP2D6 isoenzyme, plasma concentrations of vortioxetine at a dose of 10 mg/day were within the range observed in extensive metabolizers after administration of 5 and 10 mg/day.

Dose adjustment may be necessary, as with all patients, depending on individual response.

Clinical Characteristics

Indications

Treatment of major depressive disorder in adults.

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Concomitant use with non-selective monoamine oxidase inhibitors (MAOIs) or selective MAO-A inhibitors.

Interaction with other medicinal products and other forms of interaction

Vortioxetine is extensively metabolized in the liver, primarily via oxidation catalyzed by CYP2D6, and to a lesser extent by CYP3A4/5 and CYP2C9.

Effect of other medicinal products on vortioxetine activity

Irreversible non-selective MAO inhibitors

Due to the risk of serotonin syndrome, vortioxetine is contraindicated in any combination with irreversible non-selective MAO inhibitors. Treatment with vortioxetine should not be initiated earlier than at least 14 days after discontinuation of therapy with irreversible non-selective MAO inhibitors. Vortioxetine should be discontinued at least 14 days before starting treatment with irreversible non-selective MAO inhibitors.

Reversible selective MAO-A inhibitor (moclobemide)

Combination of vortioxetine with a reversible selective MAO-A inhibitor such as moclobemide is contraindicated. If combination is necessary, the medicinal product should be added starting with the lowest doses, with careful clinical monitoring for serotonin syndrome.

Reversible non-selective MAO inhibitor (linezolid)

Combination of vortioxetine with a weak reversible and non-selective MAO inhibitor such as the antibiotic linezolid is contraindicated. If combination is necessary, the medicinal product should be added starting with the lowest doses, with careful clinical monitoring for serotonin syndrome.

Irreversible selective MAO-B inhibitors (selegiline, rasagiline)

Despite a lower (compared to MAO-A inhibitors) expected risk of serotonin syndrome, combination of vortioxetine with irreversible MAO-B inhibitors such as selegiline or rasagiline should be performed with caution. Careful monitoring for serotonin syndrome during concomitant use is necessary.

Serotonergic medicinal products

Concomitant administration with serotonergic medicinal products (e.g., opioids (including tramadol) and triptans (including sumatriptan)) may lead to serotonin syndrome.

St. John’s wort

Concomitant use of serotonergic antidepressants and herbal preparations containing St. John’s wort (Hypericum perforatum) may lead to increased frequency of adverse reactions, including serotonin syndrome.

Medicinal products that lower seizure threshold

Serotonergic antidepressants may lower the seizure threshold. Caution is recommended when using other medicinal products capable of reducing the seizure threshold (such as antidepressants (TCAs, SSRIs, SNRIs), antipsychotics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion, and tramadol).

ECT (electroconvulsive therapy)

There is no clinical experience with concomitant use of vortioxetine and ECT; therefore, caution is advisable.

Inhibitors of CYP2D6

When administered together with 150 mg bupropion twice daily (a strong CYP2D6 inhibitor) for 14 days in healthy volunteers, the exposure to vortioxetine increased 2.3-fold in terms of AUC. Coadministration more frequently led to increased incidence of adverse effects when bupropion was added to vortioxetine than when vortioxetine was added to bupropion. Depending on individual patient sensitivity, when adding strong CYP2D6 inhibitors (e.g., bupropion, quinidine, fluoxetine, paroxetine) to therapy, consideration may be given to using lower doses of vortioxetine.

Inhibitors of CYP3A4, CYP2C9, and inhibitors of CYP2C19

When vortioxetine was coadministered after 6 days of treatment with ketoconazole 400 mg daily (an inhibitor of CYP3A4/5 and P-glycoprotein) or fluconazole 200 mg daily (an inhibitor of CYP2C9, CYP2C19, and CYP3A4/5) in healthy volunteers, a 1.3- and 1.5-fold increase in vortioxetine AUC was observed, respectively. Dose adjustment is not required.

No effect of a single 40 mg dose of omeprazole (an inhibitor of CYP2C19) on the pharmacokinetics of chronically administered vortioxetine was observed in healthy volunteers.

Interaction with poor CYP2D6 metabolizers

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 poor CYP2D6 metabolizers has not been specifically studied, but it is expected to result in a more pronounced increase in vortioxetine exposure in these patients compared to the moderate effects described above. Depending on individual patient response, a lower dose of vortioxetine may be considered when a strong CYP3A4 or CYP2C9 inhibitor is coadministered with poor CYP2D6 metabolizers.

Cytochrome P450 inducers

After a single 20 mg dose of vortioxetine administered 10 days after initiation of rifampicin 600 mg daily (a broad cytochrome P450 inducer) in healthy volunteers, a 72% decrease in vortioxetine AUC was observed. Depending on individual patient response, dose adjustment may be required 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 together with a single dose of ethanol 0.6 g/kg in healthy volunteers. However, as with other centrally acting agents, concomitant use of vortioxetine with alcohol is not recommended.

Acetylsalicylic acid

No effect of repeated administration of acetylsalicylic acid 150 mg daily on the pharmacokinetics of vortioxetine was observed in healthy volunteers.

Effect of vortioxetine on the activity of other medicinal products

Anticoagulants and antiplatelet agents

No significant effect on international normalized ratio, prothrombin time, or plasma R-/S-warfarin levels compared to placebo was observed during coadministration of vortioxetine with a fixed dose of warfarin in healthy volunteers. In addition, no significant inhibitory effect compared to placebo on platelet aggregation was observed during concomitant administration of aspirin 150 mg daily after vortioxetine administration in healthy volunteers. However, caution should be exercised when using vortioxetine in combination with oral anticoagulants or antiplatelet agents, or analgesic medicinal products (e.g., acetylsalicylic acid (ASA) or nonsteroidal anti-inflammatory drugs), due to the potential increased risk of bleeding via pharmacodynamic interactions.

Cytochrome P450 substrates

In vitro, vortioxetine showed no relevant potential for inhibition or induction of cytochrome P450 isoenzymes.

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

No pharmacodynamic interactions were observed. No significant impairment of cognitive function compared to placebo was observed after administration of vortioxetine together with a single 10 mg dose of diazepam.

No significant effect on sex hormone levels compared to placebo was observed after concomitant administration of vortioxetine with a combined oral contraceptive (ethinylestradiol 30 µg / levonorgestrel 150 µg).

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 concomitantly with lithium or tryptophan; therefore, concomitant use of vortioxetine with these medicinal products should be performed with caution.

Interference with urine drug screening tests

False-positive results in immunoassay screening tests for urinary metabolites of methadone have been reported in patients taking vortioxetine. Caution should be exercised when interpreting positive results of urine drug screening tests, and confirmation by an alternative analytical method (e.g., chromatographic methods) should be considered.

Special precautions for use

Use in pediatric population

Vortioxetine is not recommended for the treatment of depression in patients under 18 years of age, as safety and efficacy in this age group have not been established. In clinical studies of other antidepressants in children, suicidal behavior (suicidal attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior, and anger) occurred more frequently than in patients receiving 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 occurs. Since improvement may not occur during the first few weeks of treatment or longer, patients should be closely monitored until improvement takes place. Clinical experience indicates that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events or those presenting with marked suicidal ideation prior to treatment initiation are known to be at higher risk of suicidal thoughts or suicide attempts and require close 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 behavior compared to placebo in patients under 25 years of age.

Close monitoring of patients, and particularly 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 contact their physician immediately if such symptoms occur.

Seizures

Seizures are a potential risk associated with the use of antidepressants. Therefore, treatment with vortioxetine should be initiated cautiously in patients with a history of seizures or in patients with unstable epilepsy. Treatment should be discontinued in any patient who develops seizures or experiences an increase in seizure frequency.

Serotonin syndrome or neuroleptic malignant syndrome

Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS), potentially life-threatening conditions, may occur during treatment with vortioxetine. The risk of developing SS and NMS increases with concomitant use of serotonergic agents (including opioids and triptans), agents affecting serotonin metabolism (e.g., MAO inhibitors), antipsychotics, and other dopamine antagonists. Symptoms of SS or NMS should be carefully monitored.

Symptoms of SS include mental status changes (such as agitation, hallucinations, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, and hyperthermia), neuromuscular abnormalities (such as hyperreflexia, lack of coordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea). If such signs occur, vortioxetine should be discontinued immediately and symptomatic treatment initiated.

Mania / hypomania

Vortioxetine should be prescribed with caution in patients with a history of mania/hypomania and should be discontinued if a manic episode develops.

Aggression / agitation

Patients receiving antidepressants, including vortioxetine, may experience feelings of aggression, anger, agitation, and irritability. Close monitoring of the patient's condition is recommended. Patients (and their caregivers) should be advised to contact their physician if aggressive or agitated behavior emerges or worsens.

Bleeding

As with other serotonergic antidepressants, including vortioxetine, abnormal bleeding events such as bruising, purpura, and other hemorrhages, including gastrointestinal or gynecological bleeding, may occur. SSRIs/SSRI-SNRIs may increase the risk of postpartum hemorrhage, and this risk may potentially be associated with vortioxetine (see section "Use during pregnancy or breastfeeding"). Caution is recommended in patients taking anticoagulants and/or drugs affecting platelet function (e.g., atypical antipsychotics and phenothiazines, most TCAs, nonsteroidal anti-inflammatory drugs, acetylsalicylic acid), as well as in patients with known predisposition to bleeding or coagulation disorders.

Hyponatremia

Cases of hyponatremia, likely due to inappropriate secretion of antidiuretic hormone, have been rarely reported with SSRIs and SNRIs antidepressants. Caution should be exercised in patients at risk of hyponatremia, such as elderly patients, patients with cirrhosis, or those receiving concomitant medications that may cause hyponatremia. In patients with symptomatic hyponatremia, discontinuation of vortioxetine and appropriate medical intervention are recommended.

Glaucoma

Mydriasis has been reported in association with antidepressants, including vortioxetine. This mydriatic effect may potentiate angle closure, leading to increased intraocular pressure and acute angle-closure glaucoma. Vortioxetine should be prescribed with caution in patients with elevated intraocular pressure or those at risk of acute angle-closure glaucoma.

Elderly patients

Data on the use of vortioxetine 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 "Dosage and administration" and "Adverse reactions").

Renal or hepatic impairment

Due to the vulnerability of patients with renal or hepatic impairment and limited data on the use of vortioxetine in these subgroups, caution should be exercised when treating patients with renal or hepatic dysfunction (see sections "Dosage and administration" and "Pharmacokinetics").

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, i.e., essentially "sodium-free."

Use during pregnancy and breastfeeding

Pregnancy

Experience with the use of vortioxetine in pregnant women is limited.

Animal studies have shown reproductive toxicity.

In newborns exposed to serotonergic medicinal products late in pregnancy, symptoms such as respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, nervousness, irritability, lethargy, persistent crying, somnolence, and sleep disturbances may occur. These symptoms may be related to withdrawal effects or excessive serotonergic activity. In most cases, such complications begin immediately or shortly (<24 hours) after delivery.

Epidemiological data have shown that the use of SSRIs during pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although the association between PPHN and vortioxetine treatment has not been studied, this potential risk cannot be excluded due to the mechanism of action (increased serotonin concentrations).

Vortioxetine should be used only if the expected benefit for the mother outweighs the potential risk to the fetus.

Observational data indicate an increased risk (less than twofold) of postpartum hemorrhage following SSRI or SNRI use within one month before delivery. Although no studies have specifically investigated the association between vortioxetine treatment and postpartum hemorrhage, a potential risk exists due to the similar mechanism of action (see section "Special precautions for use").

Breastfeeding

Available preclinical data show excretion of vortioxetine and its metabolites into breast milk. Vortioxetine is expected to pass into human breast milk. Risk to the breastfed infant cannot be excluded. The decision to discontinue breastfeeding or to discontinue/continue vortioxetine therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

Animal fertility studies in males and females did not show any effect of vortioxetine on fertility, sperm quality, or mating performance.

Case reports in humans taking antidepressants of the same pharmacological class (SSRIs) have shown reversible effects on sperm quality. No effect on fertility has been observed to date.

Ability to affect reaction speed when driving or operating machinery

Arivox has no effect or negligible effect on the ability to drive or operate machinery. However, due to possible adverse reactions such as dizziness, patients should exercise caution when driving a car or operating dangerous machinery, especially at the beginning of vortioxetine treatment or when changing dosage.

Method of Administration and Dosage

Method of Administration

Arivox should be administered orally, with or without food.

The initial and maintenance dose is 10 mg once daily for adults under 65 years of age.

Depending on individual patient response, the dose may be increased up to a maximum of 20 mg vortioxetine once daily or decreased down to a minimum of 5 mg* vortioxetine once daily.

After resolution of depressive symptoms, treatment should be continued for at least 6 months to consolidate the antidepressant effect.

Discontinuation of Treatment

Gradual dose reduction should be considered to avoid discontinuation symptoms (see section "Adverse Reactions"). However, there is insufficient data to provide specific recommendations on the dose tapering regimen for patients treated with Arivox.

Special Patient Populations

Geriatric Patients

The lowest effective dose of 5 mg* vortioxetine once daily should always be used as the initial dose in patients aged ≥ 65 years. Caution is recommended when treating patients aged ≥ 65 years with doses exceeding 10 mg vortioxetine once daily, as data in this population are limited (see section "Special Warnings and Precautions for Use").

Cytochrome P450 Inhibitors

Lower doses of vortioxetine should be considered depending on individual patient response when initiating therapy with strong CYP2D6 inhibitors (e.g., bupropion, quinidine, fluoxetine, paroxetine).

Cytochrome P450 Inducers

Dose adjustment of vortioxetine should be considered depending on individual patient response when initiating therapy with cytochrome P450 inducers (e.g., rifampicin, carbamazepine, phenytoin).

Renal or Hepatic Impairment

Dose adjustment is not required in patients with renal or hepatic impairment (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

*Use vortioxetine formulations at the corresponding dosage strength.

Children

The safety and efficacy of vortioxetine for the treatment of depression in patients under 18 years of age have not been established; therefore, use is not recommended.

Overdose

Administration of vortioxetine in clinical trials within the dose range of 40 mg to 75 mg resulted in increased occurrence of adverse effects such as nausea, postural dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and facial flushing. Post-marketing experience primarily involves vortioxetine overdoses up to 80 mg. In most cases, no symptoms were reported. The most commonly observed adverse events were nausea and vomiting.

Experience with vortioxetine overdose exceeding 80 mg is limited. Following ingestion of doses several times higher than the therapeutic range, cases of seizures and serotonin syndrome have been reported.

Treatment should be symptomatic and include appropriate monitoring. Medical observation in a specialized setting is recommended.

Adverse reactions

The most common adverse reaction was nausea. The adverse reactions listed below are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and frequency not known (cannot be estimated from available data). The list is based on clinical and post-marketing data.

System, organ, class	Frequency	Adverse reaction
Immune system	Unknown*	Anaphylactic reactions
Endocrine system	Unknown*	Hyperprolactinemia, in some cases associated with galactorrhea
Metabolism and nutrition	Unknown*	Hypotension
Psychiatric	Common	Abnormal dreams
	Unknown*	Insomnia, agitation, aggression (see section "Special precautions")
Nervous system	Common	Dizziness
	Uncommon	Tremor
	Unknown*	Serotonin syndrome, headache, akathisia, bruxism, trismus, restless legs syndrome
Eye disorders	Uncommon	Blurred vision
	Rare	Mydriasis (which may precipitate acute angle-closure glaucoma – see section "Special precautions")
Cardiovascular system	Uncommon	Facial flushing
	Unknown*	Bleeding (including contusions, subcutaneous hemorrhages, epistaxis, gastrointestinal or gynecological bleeding)
Gastrointestinal system	Very common	Nausea
	Common	Diarrhea, constipation, vomiting, dyspepsia
Skin and subcutaneous tissue	Common	Pruritus, including generalized pruritus, hyperhidrosis
	Uncommon	Nocturnal sweating
	Unknown*	Edema, urticaria, rash
General disorders	Unknown*	Withdrawal syndrome

* From post-marketing data.

Nausea

Nausea as an adverse reaction was generally mild or moderate and occurred during the first two weeks of treatment. The reaction was usually transient and generally did not lead to discontinuation of therapy. Gastrointestinal reactions (including nausea) were observed more frequently in women than in men.

Elderly patients

Studies have shown that clearance was reduced in patients aged ≥65 years when administered doses of ≥10 mg of vortioxetine once daily.

When 20 mg of vortioxetine once daily was used, the incidence of nausea and constipation was higher in patients aged ≥65 years (42% and 15%, respectively) compared to patients aged <65 years (27% and 4%, respectively) (see section "Particular patient populations").

Sexual dysfunction

In clinical trials, sexual dysfunction was assessed using the Arizona Sexual Experience Scale (ASEX). Doses from 5 to 15 mg did not show differences compared to placebo. However, the 20 mg dose of vortioxetine was associated with increased sexual dysfunction (treatment-emergent sexual dysfunction) (see section "Pharmacodynamic properties"). Post-marketing reports also include cases of sexual dysfunction with vortioxetine doses below 20 mg.

Class effect

Epidemiological studies, primarily conducted in patients aged 50 years and older, suggest an increased risk of bone fractures in patients taking antidepressant medications (SSRIs or TCAs). The mechanism underlying this risk is unknown, and it is not known whether this risk also applies to vortioxetine.

Withdrawal symptoms

Withdrawal symptoms following abrupt discontinuation of vortioxetine treatment were routinely assessed in clinical trials. No clinically significant difference compared to placebo was observed in the frequency or nature of withdrawal symptoms after treatment with vortioxetine (see section "Pharmacodynamic properties"). In the post-marketing period, cases have been reported describing withdrawal symptoms, including dizziness, headache, sensory disturbances (including paraesthesia, electric shock sensations), sleep disturbances (including insomnia), nausea and/or vomiting, restlessness, irritability, agitation, fatigue, and tremor. These symptoms may occur within the first week after stopping vortioxetine.

Reporting of adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

No special storage conditions required.

Keep out of the reach of children.

Packaging

14 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Elpen Pharmaceutical Co. Inc.

Manufacturer's address and location of operations

Marathonos Avenue 95, Pikermi, 19009, Greece.