Therapeutic indications

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

Posology and method of administration

Posology

The starting and recommended dose of Brintellix is 10 mg vortioxetine once daily without regards to meals.

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

After the depressive symptoms resolve, treatment for at least 6 months is recommended for consolidation of the antidepressive response.

Treatment discontinuation

A gradual reduction in dosage may be considered to avoid the occurrence of discontinuation symptoms (see section 4.8). However, there is insufficient data to provide specific recommendations for a tapering schedule for patients treated with Brintellix

Special Population

Elderly patients

The lowest effective dose of 5 mg vortioxetine once daily should always be used as the starting dose in patients ≥ 65 years of age. Caution is advised when treating patients ≥ 65 years of age with doses higher than 10 mg vortioxetine once daily for which data are limited (see section 4.4)

Cytochrome P450 inhibitors

Reduce the dose of Brintellix by one-half when patients are receiving a CYP2D6 strong inhibitor (e.g. bupropion, fluoxetine, paroxetine or quinidine) concomitantly. The dose should be increased to the original level when the CYP2D6 inhibitor is discontinued (see section 4.5).

Cytochrome P450 inducers

Consider increasing the dose of Brintellix when strong CYP inducer (e.g. rifampicin, carbamazepine or phenytoin) is co-administered for greater than 14 days. The maximum recommended dose should not exceed three times the original dose. The dose of Brintellix should be reduced to the original level within 14 days, when the inducer is discontinued (see section 4.5).

Pediatric population

Brintellix should not be used in pediatric patients (under 18 years of age)with major depressive disorder (MDD) because efficacy has not been demonstrated (see section 5.1). The safety of Brintellix in pediatric patients is described in section 4.4, 4.8 and 5.1.

Renal or hepatic impairment

No dose adjustment is needed based on renal or hepatic function (see section 4.4 and 5.2).

Method of administration

Brintellix is for oral use.

The film-coated tablets can be taken with or without food.

Special warnings and precautions for use

Use in pediatric population

Brintellix should not be used in children and adolescents aged 7 to 17 years with MDD because efficacy has not been demonstrated (see section 5.1). In general , the adverse reaction profile of vortioxetine in children and adolescents was similar to that seen for adults except for a higher incidence of abdominal pain-related events, and a higher incidence of sucidal ideation in adolescents specifically, compared to adults (see section 4.8 and 5.1). In clinical studies in children and adolescents treated with antidepressants, suicide-related behavior (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior, anger) were more frequently observed than in those treated with placebo.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide

(suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement 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 studies of antidepressants in adult patients with psychiatric disorders

showed an increased risk of suicidal behavior with antidepressants compared to placebo, in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany treatment especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted to 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.

Seizures

Seizures are a potential risk with antidepressants. Therefore, Brintellix should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy (see section 4.5). Treatment should be discontinued in any patient who develops seizures or for whom there is an increase in seizure frequency.

Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS)

The development of a potentially life-threatening serotonin syndrome (SS) or Neuroleptic Malignant Syndrome (NMS) has been reported with serotonergic antidepressants including Brintellix, when used alone but more often when used concomitantly with other seotonergic drugs (including Opioids and triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John’s Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also other, such as linezolid and intravenous methylene blue). Patients should be monitored for the emergence of signs and symptoms of SS or NMS

Serotonin Syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia and incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting and diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of Brintellix with MAOIs intended to treat psychiatric disorders is contraindicated. Brintellix should also not be started in a patient who is being treated with MAOIs such as linezolid and intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid and intravenous methylene blue in a patient taking Brintellix. Brintellix should be discontinued before initiating treatment with the MAOI (see section 4.3 and 4.5).

If concomitant use of Brintellix with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone ,tryptophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increase. Treatment with Brintellix and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Angle Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs, including Brintellix, may trigger an angle closure attack in a patient with anatomically narrow angles who dose not have a patent iridectomy.

Mania/hypomania

Brintellix should be used with caution in patients with a history of mania/hypomania and should be discontinued in any patient entering a manic phase.

Aggression/agitation

Patients treated with antidepressants, including vortioxetine, may also experience feelings of aggres-sion, anger, agitation and irritability. Patient’s condition and disease status should be closely monitored. Patients (and caregivers of patients) should be alerted to seek medical advice, if aggres-sive/agitated behavior emerges or aggravates.

Hemorrhage

Bleeding abnormalities, such as ecchymoses, purpura and other hemorrhagic events, such as gastrointestinal or gynaecological bleeding, have been reported rarely with the use of antidepressants with serotonergic effect, including vortioxetine. SSRIs/SNRIs may increase the risk of postpartum hemorrhage, and this risk could potentially apply also to vortioxetine (see section 4.6). Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function [e.g., atypical antipsychotics and phenothiazines, most tricyclic antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid (ASA)] (see section 4.5) and in patients with known bleeding tendencies/disorders.

Hyponatraemia

Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported rarely with the use of antidepressants with serotonergic effect (SSRIs, SNRIs). Caution should be exercised in patients at risk, such as the elderly, patients with cirrhosis of the liver or patients concomitantly treated with medications known to cause hyponatraemia.

Discontinuation of Brintellix should be considered in patients with symptomatic hyponatraemia and appropriate medical intervention should be instituted.

Glaucoma

Mydriasis has been reported in association with use of antidepressants, including vortioxetine. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma. Caution is advised when prescribing vortioxetine to patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.

Elderly

Data on the use of Brintellix in elderly patients with major depressive episodes are limited. Therefore, caution should be exercised when treating patients ≥ 65 years of age with doses higher than 10 mg vortioxetine once daily impairment. Caution should therefore be exercised (see section 5.2).

Renal or hepatic impairment

Given that subjects with renal or hepatic impairment are vulnerable and given that the data on the use of Brintellix in these subpopulations are limited, caution should be exercised when treating these patients.

Limited data are available for patients with severe renal impairment. Caution should therefore be exercised (see section 4.2 and 5.2).

Brintellix contains Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Interaction with other medicinal products and other forms of interaction

Vortioxetine is extensively metabolized in the liver primarily through oxidation and subsequent glucuronic acid conjugation. In vitro, the cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 are involved in the metabolism of vortioxetine (see section 5.2).

Potential for other medicinal products to affect vortioxetine

Irreversible non-selective MAOIs

Due to the risk of Serotonin Syndrome, vortioxetine is contraindicated in any combination with irreversible non-selective MAOIs. Vortioxetine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible non-selective MAOI. Vortioxetine must be discontinued for at least 14 days before starting treatment with an irreversible non-selective MAOI (see section 4.3).

Reversible, selective MAO-A inhibitor (moclobemide)

The combination of vortioxetine with a reversible and selective MAO-A inhibitor, such as moclobemide, is contraindicated (see section 4.3). If the combination proves necessary, the added medicinal product should be given with minimum dosage and under close clinical monitoring for Serotonin Syndrome (see section 4.4).

Reversible, non-selective MAOI (linezolid)

The combination of vortioxetine with a weak reversible and non-selective MAOI, such as the

antibiotic linezolid, is contraindicated (see section 4.3). If the combination proves necessary, the added medicinal product should be given with minimum dosage and under close clinical monitoring for Serotonin Syndrome (see section 4.4).

Irreversible, selective MAO-B inhibitor (selegiline, rasagiline)

Although a lower risk of Serotonin Syndrome is expected with selective MAO-B inhibitors than with MAO-A inhibitors, the combination of vortioxetine with irreversible MAO-B inhibitors, such as selegiline or rasagiline should be exercised with caution. Close monitoring for Serotonin Syndrome is necessary if used concomitantly (see section 4.4).

Serotonergic medicinal products

Co-administration of medicinal products with serotonergic effect e.g. opioids (including tramadol) and triptans (including sumatriptan  may lead to Serotonin Syndrome (see section 4.4).

St. John’s wort

Concomitant use of antidepressants with serotonergic effect and herbal remedies containing St. John´s wort (Hypericum perforatum) may result in a higher incidence of adverse reactions including Serotonin Syndrome (see section 4.4).

Medicinal products lowering the seizure threshold

Antidepressants with serotonergic effect can lower the seizure threshold. Caution is advised when concomitantly using other medicinal products capable of lowering the seizure threshold [(e.g. antidepressants (tricyclics, SSRIs, SNRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquin, bupropion, tramadol)] (see section 4.4).

ECT (electroconvulsive therapy)

There is no clinical experience with concurrent administration of vortioxetine and ECT, therefore caution is advisable.

Cytochrome P450 inhibitors

The exposure to vortioxetine increased 2.3-fold for Area Under Curve (AUC) when vortioxetine

10 mg/day was co-administered with bupropion (a strong CYP2D6 inhibitor 150 mg twice daily) for

14 days in healthy subjects. Co-administration resulted in a higher incidence of adverse reactions when bupropion was added to vortioxetine than when vortioxetine was added to bupropion. Depending on individual patient response, a lower dose of vortioxetine may be considered if strong

CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to vortioxetine treatment (see section 4.2).

When vortioxetine was co-administered following 6 days of ketoconazole 400 mg/day (a CYP3A4/5 and P-glycoprotein inhibitor) or following 6 days of fluconazole 200 mg/day (a CYP2C9, CYP2C19, and CYP3A4/5 inhibitor) in healthy subjects, a 1.3-fold and 1.5-fold increase, respectively in vortioxetine AUC was observed. No dose adjustment is needed.

No inhibitory effect of 40 mg single-dose omeprazole (CYP2C19 inhibitor) was observed on the multiple-dose pharmacokinetics of vortioxetine in healthy subjects.

Co-administration of strong inhibitors of CYP3A4 and CYP2C9 to CYP2D6 poor metabolisers has not been investigated specifically, but it is anticipated that it will lead to increased exposure of

vortioxetine in these patients (see section 5.2).

Cytochrome P450 inducers

When a single dose of 20 mg vortioxetine was co-administered following 10 days of rifampicin

600 mg/day (a broad inducer of CYP isozymes) in healthy subjects, a 72% decrease in AUC of vortioxetine was observed. Depending on individual patient response, a dose adjustment may be considered if a broad cytochrome P450 inducer (e.g. rifampicin, carbamazepine, phenytoin) is added to vortioxetine treatment (see section 4.2).

Alcohol

May enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk

of psychomotor impairment may be enhanced. Patients receiving selective serotonin reuptake inhibitors should be advised to avoid alcohol. Monitor for the increased psychomotor impairment in patients who consume alcohol during treatment

No effect on the pharmacokinetics of vortioxetine or ethanol and no significant impairment, relative to placebo, in cognitive function was observed when vortioxetine single doses of 20 mg or 40 mg was co-administered with a of single dose of ethanol (0.6 g/kg) in healthy subjects.

Acetylsalicylic acid

No effect of multiple doses of acetylsalicylic acid 150 mg/day on the multiple-dose pharmacokinetics of vortioxetine was observed in healthy subjects.

Potential for vortioxetine to affect other medicinal products

Anticoagulants and antiplatelet medicinal products

No significant effects, relative to placebo, were observed in INR, prothrombin or plasma

R-/S-warfarin values following co-administration of multiple doses of vortioxetine with stable doses of warfarin in healthy subjects. Also, no significant inhibitory effect, relative to placebo, on platelet aggregation or pharmacokinetics of acetylsalicylic acid or salicylic acid was observed when acetylsalicylic acid 150 mg/day was co-administered following multiple doses of vortioxetine administration in healthy subjects. However, as for other serotonergic medicinal products, caution should be exercised when vortioxetine is combined with oral anticoagulants or antiplatelet medicinal products or medicines used for pain relief (e.g. acetylsalicylic acid (ASA) or NSAIDs), due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction (see section 4.4).

Potential pharmacokinetic interactions

Cytochrome P450 substrates

In vitro, vortioxetine did not show any relevant potential for inhibition or induction of cytochrome P450 isozymes (see section 5.2).

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

No pharmacodynamic interactions were observed. No significant impairment, relative to placebo, in cognitive function was observed for vortioxetine following co-administration with single 10 mg dose of diazepam. No significant effects, relative to placebo, were observed in the levels of sex hormones following co-administration of vortioxetine with a combined oral contraceptive (ethinyl estradiol

30 µg/ levonorgestrel 150 µg).

Lithium, tryptophan

No clinically relevant effect was observed during steady-state lithium exposure following co- administration with multiple doses of vortioxetine in healthy subjects. However, there have been reports of enhanced effects when antidepressants with serotonergic effect have been given together with lithium or tryptophan, therefore concomitant use of vortioxetine with these medicinal products should be undertaken with caution.

Interference with urine drug screens

There have been reports of false positive results in urine enzyme immunoassays for methadone in patients who have taken vortioxetine. Caution should be exercised in the interpretation of positive urine drug screen results, and confirmation by an alternative analytical technique (e.g., chromatographic methods) should be considered.

Fertility, pregnancy and lactation

Pregnancy

Pregnancy Category C

There are limited data from the use of vortioxetine in pregnant women. Vortioxetine should not be

used during pregnancy unless the clinical condition of the woman requires treatment with vortioxetine.

The following symptoms may occur in the newborn after maternal use of aserotonergic medicinal product in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either discontinuation effects or excess serotonergic activity. In the majority of instances, such complications began immediately or soon (<24 hours) after delivery.

Epidemiological data suggest that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN with vortioxetine treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).

Animal studies did not demonstrate a teratogenic effect of vortioxetine, but effects on foetal weight and delayed ossification were seen (see section 5.3).

Observational data have provided evidence of an increased risk (less than 2-fold) of postpartum hemorrhage following exposure to an SSRI or SNRI within the month prior to birth. Although no studies have investigated an association between vortioxetine treatment and postpartum hemorrhage, there is a potential risk, taking into account the related mechanism of action (See section 4.4)

Breast-feeding

Available data in animals have shown excretion of vortioxetine/ vortioxetine metabolites in milk. It is expected that vortioxetine will be excreted into human milk (see section 5.3).

A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Brintellix treatment taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Fertility studies in male and female rats showed no effect of vortioxetine on fertility, sperm quality or mating performance (see section 5.3).

Human case reports with medicinal products from the related pharmacological class of antidepressants (SSRIs) have shown an effect on sperm quality that is reversible. Impact on human fertility has not been observed so far.

Effects on ability to drive and use machines

No significant impairment, relative to placebo, in driving performance, cognitive function or other psychomotor skills (using a battery of neuropsychological tests) was observed when healthy subjects were administered single and multiple doses of 10 mg/day vortioxetine. However, patients should exercise caution when driving or operating hazardous machinery.

Undesirable effects

Adverse reactions are listed below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).  The list is based on information from clinical trials and post-marketing experience.

* Based on post-marketing cases

Clinical studies experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

Patient exposure

Brintellix was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD

who participated in pre-marketing clinical studies; 2616 of those patients were exposed to Brintellix in

6 to 8 weeks, placebo-controlled studies at dose renging from 5 mg to 20 mg once daily and 204 patients were exposed to Brintellix in a 24 week to 64 week placebo-controlled maintenance study at doses of 5 mg to 10 mg once daily. Patients from the 6 to 8 week studies continued into 12 month open-label studies. Of the 2586 patients were exposed to at least one dose of Brintellix in open-label studies, 1727 were exposed to Brintellix for six months and 885 were exposed for at least one year. Adverse reactions reported as reason for discontinuation of treatment

In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received Brintellix 5

mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5 %, 6 % , 8 % and 8 %, respectively, compared to 4 % of placebo-treated patients, Nausea was the most common adverse reaction reported as reason for discontinuation.

Common adverse reactions in placebo-controlled MDD studies

The most commonly observed adverse reaction in MDD patients treated with Brintellix in 6 to 8

weeks placebo-controlled studies (incidence > 5 % and at least twice the rate of placebo) were nausea, constipation and vomiting.

Table 1 shows the incidence of common adverse reactions that occurred in ≥2 % of MDD patients treated with any Brintellix dose and at least 2 % more frequently than in placebo-treated patients in the 6 to 8 week placebo-controlled studies.

  * Includes pruritus generalised

Nausea

Nausea was the most common adverse reaction and its frequency was dose-related (Table 2). It was usually considered mild or moderate in intensity and the median duration was 2 weeks. Nausea was more common in females than males. Nausea

most commonly occurred   in  the  first  week of  BRINTELLIX treatment  with  15 to 20% of  patients experiencing  nausea after  I  to 2 days of treatment.

Approximately 10% of patients taking BRINTELLIX 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo- controlled study.

Description of selected adverse reactions

Elderly patients

For doses ≥10 mg vortioxetine once daily, the withdrawal rate from the studies was higher in patients

aged ≥65 years.

For doses of 20 mg vortioxetine once daily, the incidences of nausea and constipation were higher in patients aged ≥65 years (42% and 15%, respectively) than in patients aged <65 years (27% and 4%, respectively)(see section 4.4).

Sexual dysfunction

Difficulties in sexual desire, sexual performance  and sexual satisfaction  often occur as manifestations  of  psychiatric  disorders,  but they  may also be consequences of pharmacologic treatment.

In the MDD 6 to 8 week controlled  trials of BRINTELLIX,  voluntarily reported adverse reactions  related  to sexual  dysfunction  were captured  as  individual event  terms.  These event terms have been aggregated and the overall incidence was as  follows. In  male patients  the overall  incidence  was  3%,  4%,  4%,  5%  in BRINTELLIX  5  mg/day,  l 0 mg/day, 15  mg/day,  20  mg/day,  respectively, compared  to  2%  in  placebo.  In female patients, the overall incidence was <I%,

1%, <1%, 2%  in BRINTELLIX  5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to <1% in placebo.

Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively  in seven placebo- controlled trials. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women),  4) ease of reaching orgasm, and 5) orgasm satisfaction.

The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table2 shows the incidence of patients that developed treatment-emergent sexual dysfunction when treated with BRINTELLIX or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects.

* Incidence based on number of subjects with sexual dysfunction during the study I number of subjects without sexual dysfunction at baseline. Sexual dysfunction was defined as a subject scoring any of the following on the ASEX scale at two consecutive visits during the study: 1) total score ≥19;2) any single item ≥5;3) three or more items each with a score ≥4

† Sample size for each dose group is the number of patients (females:  males) without sexual dysfunction at baseline.

In the post-marketing setting cases of sexual dysfunction have also been reported with doses of vortioxetine below 20 mg.

Class effect

Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving a drug from related pharmacological classes of antidepressants (SSRIs or TCAs). The mechanism behind this risk is unknown, and it is not known if this risk is also relevant for vortioxetine.

Pediatric population

A total of 304 children aged 7 to 11 years and 308 adolescents aged 12 to 17 years with major depressive disorder (MDD) were treated with vortioxetine in two double-blind, placebo-controlled studies, respectively. In general, the adverse reaction profile of vortioxetine in children and adolescents was similar to that observed in adults except for a higher incidence of abdominal pain-related events, and a higher incidence of suicidal ideation in adolescents specially, compared to adults (see section 5.1).

Two long-term open-label extension studies were performed with vortioxetine doses of 5 to 20 mg/day, and with a treatment duration of 6 months (N=662) and 18 months (N=94), respectively. Overall, the safety and tolerability profile of vortioxetine in the paediatric population after long-term use was comparable to what has been observed after short-term use.

Symptoms upon discontinuation of vortioxetine treatment

In the clinical studies, discontinuation symptoms were systematically evaluated following abrupt cessation of vortioxetine treatment. There was no clinically relevant difference to placebo in the incidence or nature of the discontinuation symptoms after treatment with vortioxetine (see section 5.1). Cases describing discontinuation symptoms have been reported in the post-marketing setting and have included symptoms such as dizziness, headache, sensory disturbances (including paraesthesia, electric shock sensations), sleep disturbances (including insomnia), nausea and/or vomiting, anxiety, irritability, agitation, fatigue and tremor. These symptoms may occur within the first week of vortioxetine discontinuation

Reporting of suspected 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 professionals are asked to report any suspected adverse reactions via the national reporting system

Saudi Arabia:

Other GCC States:

Adverse Reactions Following Abrupt Discontinuation of BRINTELLIX Treatment

Discontinuation symptoms have been prospectively evaluated in patients taking BRINTELLIX

10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and

Symptoms (DESS) scale in clinical trials. Some patients experienced discontinuation

symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger,

dizziness, and runny nose in the first week of abrupt discontinuation of BRINTELLIX 15 mg/day

and 20 mg/day.

Laboratory Tests

BRINTELLIX has not been associated with any clinically important changes in laboratory test

parameters in serum chemistry (except sodium), hematology and urinalysis as measured in

the 6 to 8 week placebo-controlled studies. Hyponatremia has been reported with the

treatment of BRINTELLIX [see Special warnings and precautions for use 4.4]. In the six month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12 week, open-label phase, there were no clinically important changes in labtest parameters between BRINTELLIX and placebo-treated patients.

Weight

BRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies. In the 6-month, double blind, placebo-controlled phase of a long-term study in patients who had responded to BRINTELLIX during the initial 12-week, open-label phase, there was no significant effect on body weight between BRINTELLIX and placebo- treated patients.

Vital Signs

BRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.

Other Adverse Reactions Observed in Clinical Studies The following listing does not include reactions:

1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote,

3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo.

Ear and labyrinth disorders — vertigo

Gastrointestinal disorders — dyspepsia

Nervous system disorders — dysgeusia

Vascular disorders — flushing

Ingestion of vortioxetine in the dose range of 40 to 75 mg has caused an aggravation of the following adverse reactions: nausea, postural dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence and flushing.

Post-marketing experience mainly concerns vortioxetine overdoses of up to 80 mg. In the majority of cases, no symptoms or mild symptoms were reported. The most frequently reported symptoms were nausea and vomiting.

There is limited experience with vortioxetine overdoses above 80 mg. Following dosages several fold higher than the therapeutic dose range, events of seizure and serotonin syndrome have been reported.

Management of overdose should consist of treating clinical symptoms and relevant monitoring. Medical follow-up in a specialized environment is recommended.

Pharmacodynamic properties

Pharmacotherapeutic group: Psychoanaleptics; Other antidepressants, ATC-code: N06AX26

Mechanism of action

The mechanism of action of vortioxetine is thought to be related to its direct modulation of serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter. Non-clinical data indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter, leading to modulation of neurotransmission in several systems, including the serotonin, norepinephrine, dopamine, histamine, acetylcholine, GABA and glutamate systems. This multimodal activity is considered responsible for the antidepressant and anxiolytic-like effects and the improvement of cognitive function, learning and memory observed with vortioxetine in animal studies. In addition, a nonclinical behavioural study in male animals indicates that vortioxetine does not induce sexual dysfunction. However, the precise contribution of the individual targets to the observed pharmacodynamic profile remains unclear and caution should be applied when extrapolating animal data directly to man.

In humans, two positron emission tomography (PET) studies have been conducted using 5-HT transporter ligands (11C-MADAM or 11C-DASB) to quantify the 5-HT transporter occupancy in the brain across different dose levels. The mean 5-HT transporter occupancy in the specific regions of interest was approximately 50% at 5 mg/day, 65% at 10 mg/day and increased to above 80% at

20 mg/day. Vortioxetine has shown clinical antidepressant effects at 5-HT transporter occupancies as low as 50%.

Clinical efficacy and safety

The efficacy and safety of vortioxetine have been studied in a clinical program that included more than 6,700 patients, of whom more than 3,700 were treated with vortioxetine in short-term

(≤12 weeks) studies in major depressive disorder (MDD). Twelve double-blind, placebo controlled,

6/8-week, fixed-dose studies have been conducted to investigate the short-term efficacy of vortioxetine in MDD both in adults and in the elderly. The efficacy of vortioxetine was demonstrated across 9 of the 12 studies, as measured by improvement in the Montgomery and Åsberg Depression Rating Scale (MADRS)  or Hamilton Depression Rating Scale 24-item (HAM-D24 ) total score, and supported by clinical relevance as demonstrated by the proportions of responders and remitters and the improvement in Clinical Global Impression – Global Improvement (CGI-I) score.

The efficacy of vortioxetine increased with increasing dose. Furthermore, vortioxetine, in the dose range of 5-20 mg/day, demonstrated efficacy on the broad range of depressive symptoms (assessed by improvement in all MADRS single–item scores) and on the anxiety symptoms in depression (assessed using the HAM-A total score).

Maintenance

The maintenance of antidepressant efficacy was demonstrated in a relapse-prevention study. Patients

in remission after an initial 12-week open-label treatment period with vortioxetine were randomised to vortioxetine 5 or 10 mg/day or placebo and observed for relapse during a double-blind period of at least 24 weeks (24 to 64 weeks). Vortioxetine was superior (p=0.004) to placebo on the primary outcome measure, the time to relapse of MDD, with a hazard ratio of 2.0; that is, the risk of relapse was two times higher in the placebo group than in the vortioxetine group.

Elderly

In the double-blind, placebo-controlled, 8-week, fixed-dose study in elderly (aged ≥65 years) depressed patients, vortioxetine 5 mg/day was superior to placebo as measured by improvement in the MADRS and HAM-D24 total scores.

In the dose range of 5 to 20 mg/day vortioxetine, efficacy and tolerability in the elderly was in line with the results in the adult population.

Patients with severe depression or high levels of anxiety symptoms

Antidepressant efficacy was also demonstrated in severely depressed patients (baseline MADRS total score ≥30) and in depressed patients with a high level of anxiety symptoms (baseline HAM-A total score ≥20) in short-term studies including the study in the elderly and in the long-term relapse- prevention study. Vortioxetine was effective in these patients.

Patients with inadequate response to SSRI/SNRI treatment

In a 12-week, double-blind, flexible-dose, comparative study in patients with moderate to severe depression who switched antidepressant treatment after an inadequate response to an SSRI/SNRI for the current episode vortioxetine 10-20 mg/day was statistically significantly better than agomelatine

25-50 mg/day as measured by improvement in the MADRS total score. The clinical relevance was

supported by the proportion of remitters and improvement in CGI-I and Sheehan Disability Scale

(SDS) scores.

Cognitive dysfunction in depression

In a short-term study in MDD in the elderly (≥65 years of age), vortioxetine (5 mg/day) demonstrated

positive effects relative to placebo on a neuropsychological test of executive function, processing speed, and attention, the Digit Symbol Substitution Test (DSST), and on a test of learning and memory, the Rey Auditory Verbal Learning Test (RAVLT), whereas the active reference duloxetine separated from placebo on the RAVLT only.

Further, vortioxetine was superior to placebo in a range of neuropsychological tests involving the above-mentioned cognitive processes in a study in MDD in adults (<65 years of age). Vortioxetine (10 and 20 mg/day) was superior to placebo on the primary outcome measure, a composite cognition score comprising the two neuropsychological tests, the DSST and the RAVLT. An improved performance was seen across all secondary measures of cognitive performance and on a patient-reported outcome

of cognitive function.

In both studies, the effect of vortioxetine was mainly an independent effect on cognitive performance rather than an indirect effect through improvement of depressive symptoms.

Health-related quality of life and overall functioning

Vortioxetine was superior to placebo in health-related quality of life, as assessed using the SF-36

Mental Component Summary and the Quality of Life Enjoyment Satisfaction Questionnaire total and life satisfaction scores. This was supported by clinically relevant improvements in the overall health rating as measured using EQ-5D (EuroQol index) and in the overall functioning as assessed using the Sheehan Disability Scale (SDS) total score in the areas of work, social life, and family life versus placebo or an active comparator (agomelatine). Furthermore, the superior effects relative to placebo in health related quality of life were maintained in the long-term relapse prevention study.

Tolerability and safety

The safety and tolerability of vortioxetine have been established in short- and long-term studies across the dose range of 5 to 20 mg/day. For information on undesirable effects, see section 4.8.

Vortioxetine did not increase the incidence of insomnia or somnolence relative to placebo.

In clinical short- and long-term placebo-controlled studies, potential discontinuation symptoms were systematically evaluated after abrupt treatment cessation of vortioxetine.

There was no clinically relevant difference to placebo in the incidence or nature of the discontinuation symptoms after either short-term (6-12 weeks) or long-term (24-64 weeks) treatment with vortioxetine.

The incidence of self-reported adverse sexual reactions was low and similar to placebo in clinical short- and long-term studies with vortioxetine. In studies using the Arizona Sexual Experience Scale (ASEX), the incidence of treatment-emergent sexual dysfunction (TESD) and the ASEX total score showed no significant difference to placebo in symptoms of sexual dysfunction for doses 5-20 mg/day, however higher doses were associated with a numerical increase in TESD.

The effect of vortioxetine on sexual function was further evaluated in an 8-week, double-blind, flexible-dose, comparative study (n=424) versus escitalopram in patients treated for at least 6 weeks with an SSRI (citalopram, paroxetine, or sertraline), with a low level of depressive symptoms (baseline CGI-S ≤ 3) and TESD induced by the prior SSRI treatment. Vortioxetine 10-20 mg/day had statistically significantly less TESD than escitalopram 10-20 mg/day as measured by change in the CSFQ-14 total score (2.2 points, p=0.013) at week 8. The proportion of responders 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.

Vortioxetine had no effect relative to placebo on body weight, heart rate, or blood pressure in clinical short- and long-term studies.

No clinically significant changes were observed in hepatic and renal assessments in clinical studies.

Vortioxetine has not shown any clinically significant effect on ECG parameters, including the QT,

QTc, PR and QRS intervals, in patients with MDD. In a thorough QTc study in healthy subjects at

doses up to 40 mg daily, no potential for the prolongation of the QTc interval was observed.

Paediatric population

Two short-term, randomised, double-blind, placebo-controlled, fixed-dose (vortioxetine 10 mg/day and 20 mg/day), active-referenced (fluoxetine), efficacy and safety studies have been conducted; one in children aged 7 to 11 years with MDD, and one in adolescents aged 12 to 17 years with MDD. The studies included a 4-week single-blind placebo lead-in period with standardized psychosocial intervention (treated patients in children study N=677, adolescent study N=777) and only non-responders from the lead-in period were randomised (children study N=540, adolescent study N=616).

In the study in children aged 7 to 11 years, the average effect of the two vortioxetine doses 10 and 20 mg/day was not statistically significantly different from placebo based on the Children´s Depression Rating Scale-Revised (CDRS-R) total score at week 8, nor was the active reference (fluoxetine 20 mg/day), nor did the individual vortioxetine doses (10 and 20mg/day) show a nominally significant difference from placebo. In general, the adverse event profile of vortioxetine in children was similar to that seen for adults, except for higher incidence of abdominal pain reported in children. Discontinuation due to adverse events was 2.0% in patients treated with vortioxetine 20 mg/day, 1.3% for vortioxetine 10 mg/day, 0.7% for placebo, and no discontinuations for fluoxetine. The most commonly reported adverse events in the vortioxetine treatment groups were nausea, headache, vomiting, dizziness, and abdominal pain. The incidence of nausea, vomiting and abdominal pain was higher in the vortioxetine groups than in the placebo group. Suicidal ideation and behaviour were reported as adverse events during the 4-week single-blind lead-in period (placebo 2/677 [0.3%]), and during the 8-week treatment period (vortioxetine 10 mg/day 1/149 [0.7%], placebo 1/153 [0.7%]). In addition, the event ‘non-specific active suicidal thoughts’ was reported in the C-SSRS in 5 patients during the 8-week treatment period (vortioxetine 20 mg/day 1/153 [0.7%], placebo 1/153 [0.7%] and fluoxetine 3/82 [3.7%]). Suicidal ideation and behaviour as measured by Columbia-Suicide Severity Rating Scale (C-SSRS) was similar across treatment groups.

In the study in adolescents aged 12 to 17 years neither vortioxetine 10 mg/day nor 20 mg/day was statistically significantly superior to placebo based on the Children´s Depression Rating Scale-Revised (CDRS-R) total score. The active reference (fluoxetine 20 mg/day) separated statistically from placebo on the CDRS-R total score. In general, the adverse reaction profile of vortioxetine in adolescents was similar to that seen for adults except for higher incidences reported in adolescents than in adults for abdominal pain- and suicidal ideation. Discontinuation due to adverse events (mostly due to suicidal ideation, nausea and vomiting) was highest in patients treated with vortioxetine 20 mg/day (5.6%) as compared to vortioxetine 10 mg/day (2.7%), fluoxetine (3.3%), and placebo (1.3%). The most commonly reported adverse events in the vortioxetine treatment groups were nausea, vomiting and headache. Suicidal ideation and behavior were reported as adverse events both during the 4-week single-blind lead-in period (placebo 13/777 [1.7%]), and during the 8-week treatment period (vortioxetine 10 mg/day 2/147 [1.4%], vortioxetine 20 mg/day 6/161 [3.7%], fluoxetine 6/153 [3.9%], placebo 0/154 [0%]). Suicidal ideation and behavior as measured by C-SSRS was similar across treatment groups.

Clinical studies on the use of vortioxetine in children and adolescents have not been conducted; therefore, the safety and efficacy of vortioxetine in the paediatric population have not been established (see section 4.2).

Brintellix should not be used in paediatric patients (under 18 years of age) with major depressive disorder (see section 4.2)

Pharmacokinetic properties

Absorption

Vortioxetine is slowly but well absorbed after oral administration and the peak plasma concentration is reached within 7 to 11 hours. Following multiple dosing of 5, 10, or 20 mg/day, mean Cmax values of 9 to 33 ng/mL were observed. The absolute bioavailability is 75%. No effect of food on the

pharmacokinetics was observed (see section 4.2).

Distribution

The mean volume of distribution (Vss ) is 2,600 L, indicating extensive extravascular distribution. Vortioxetine is highly bound to plasma proteins (98 to 99%) and the binding appears to be independent of vortioxetine plasma concentrations.

Biotransformation

Vortioxetine is extensively metabolised in the liver, primarily through oxidation and subsequent glucuronic acid conjugation.

In vitro, the cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8, and CYP2B6 are involved in the metabolism of vortioxetine.

No inhibitory or inducing effect of vortioxetine was observed in vitro for the CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5. Vortioxetine is a poor P-gp substrate and inhibitor.

The major metabolite of vortioxetine is pharmacologically inactive.

Elimination

The mean elimination half-life and oral clearance are 66 hours and 33 L/h, respectively.

Approximately 2/3 of the inactive vortioxetine metabolites are excreted in the urine and approximately

1/3 in the faeces. Only negligible amounts of vortioxetine are excreted in the faeces. Steady-state plasma concentrations are achieved in approximately 2 weeks.

Linearity/non-linearity

The pharmacokinetics are linear and time independent in the dose range studied (2.5 to 60 mg/day).

In accordance with the half-life, the accumulation index is 5 to 6 based on AUC0-24h following multiple doses of 5 to 20 mg/day.

Special populations

Elderly

In elderly healthy subjects (aged ≥65 years; n=20), the exposure to vortioxetine increased up to 27%

(Cmax and AUC) compared to young healthy control subjects (aged ≤45 years) after multiple doses of 10 mg/day. No dose adjustment is needed (see section 4.2).

Renal impairment

Following a single dose of 10 mg vortioxetine, renal impairment estimated using the Cockcroft-Gault formula (mild, moderate, or severe; n=8 per group) caused modest exposure increases (up to 30%), compared to healthy matched controls. 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; n=8) following a single 10 mg dose of vortioxetine. No dose adjustment is needed based on renal function   (see section 4.2 and 4.4).

Hepatic impairment

The pharmacokinetics in subjects (N = 6-8) with mild, moderate, or severe hepatic impairment (Child-Pugh Criteria A, B, or C, respectively) were compared to healthy volunteers. The changes in AUC were less than 10% lower in subjects with mild or moderate hepatic impairment, and 10% higher in those with severe hepatic impairment. The changes in Cmax were less than 25% lower in all groups. No dose adjustment is needed based on hepatic function (see section 4.2 and 4.4).

CYP2D6 poor metabolisers

The plasma concentration of vortioxetine was approximately two times higher in CYP2D6 poor metabolisers than in extensive metabolisers. In the presence of strong CYP3A4/2C9-inhibitors, the exposure could potentially be higher (see section 4.5). As for all patients, depending on individual patient response, a dose adjustment may be considered (see section 4.2).

Pediatric population

Pharmacokinetics of vortioxetine in paediatric patients with major depressive disorder following oral administration of 5 to 20 mg once daily was characterized using population modeling analyses based on data from a pharmacokinetic study (7-17 years) and two efficacy and safety studies (7-17 years). The pharmacokinetics of vortioxetine in paediatric patients was similar to that observed in adult patients.

Preclinical safety data

Administration of vortioxetine in the general toxicity studies in mice, rats and dogs was mainly associated with CNS-related clinical signs. These included salivation (rat and dog), pupil dilatation (dog), and one episode of convulsions in each of two dogs. A no-effect level for convulsions was established with a corresponding safety margin of 5 considering the maximum recommended therapeutic dose of 20 mg/day. Target organ toxicity was restricted to kidneys (rats) and liver (mice and rats). The changes in the kidney in rats (glomerulonephritis, renal tubular obstruction, crystalline material in renal tubule) and in the liver of mice and rats (hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, crystalline material in bile ducts) were seen at exposures more than 10- fold (mice) and 2-fold (rats) the human exposure at the maximum recommended therapeutic dose of

20 mg/day. These findings were mainly attributed to rodent-specific vortioxetine-related crystalline

material obstruction of the renal tubules and the bile ducts, respectively, and considered of low risk to humans.

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

Based on results from conventional 2-year carcinogenicity studies in mice or rats, vortioxetine is not considered to pose a risk of carcinogenicity in humans.

Vortioxetine had no effect on rat fertility, mating performance, reproductive organs, or sperm morphology and motility. Vortioxetine was not teratogenic in rats or rabbits, but reproductive toxicity in terms of effects on foetal weight and delayed ossification were seen in the rat at exposures more than 10-fold the human exposure at the maximum recommended therapeutic dose of 20 mg/day. Similar effects were seen in the rabbit at sub-therapeutic exposure.

In a pre- and post-natal study in rats, vortioxetine was associated with increased pup mortality, reduced bodyweight gain, and delayed pup development at doses that did not result in maternal toxicity and with associated exposures similar to those achieved in humans following administration of vortioxetine 20 mg/day (see section 4.6).

Vortioxetine-related material was distributed to the milk of lactating rats (see section 4.6).

In juvenile toxicity studies in rats, all vortioxetine treatment-related findings were consistent with those noted in adult animals.

List of excipients

Tablet core

Mannitol

Microcrystalline cellulose

Hydroxypropylcellulose

Sodium starch glycolate (type A) Magnesium stearate

10 mg Tablet coating

Hypromellose

Macrogol 400

Titanium dioxide (E171) Iron oxide yellow (E172)

20 mg Tablet coating

Hypromellose

Macrogol 400

Titanium dioxide (E171) Iron oxide red (E172)

Not applicable.

Do not store above 30 °C.

Blister: Transparent; PVC/PVdC/aluminium blister. Pack size of 28 film-coated tablets.

Not all strengths or pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.