BRINTELLIX 10mg tablets medication leaflet

Brintellix 5 mg film-coated tablets

Brintellix 10 mg film-coated tablets

Brintellix 15 mg film-coated tablets

Brintellix 20 mg film-coated tablets

Brintellix 5 mg film-coated tablets

Each film-coated tablet contains vortioxetine hydrobromide equivalent to 5 mg vortioxetine.

Brintellix 10 mg film-coated tablets

Each film-coated tablet contains vortioxetine hydrobromide equivalent to 10 mg vortioxetine.

Brintellix 15 mg film-coated tablets

Each film-coated tablet contains vortioxetine hydrobromide equivalent to 15 mg vortioxetine.

Brintellix 20 mg film-coated tablets

Each film-coated tablet contains vortioxetine hydrobromide equivalent to 20 mg vortioxetine.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Brintellix 5 mg film-coated tablets

Pink, almond-shaped (5 x 8.4 mm) film-coated tablet engraved with “TL” on one side and “5” on theother side.

Brintellix 10 mg film-coated tablets

Yellow, almond-shaped (5 x 8.4 mm) film-coated tablet engraved with “TL” on one side and “10” onthe other side.

Brintellix 15 mg film-coated tablets

Orange, almond-shaped (5 x 8.4 mm) film-coated tablet engraved with “TL” on one side and “15” onthe other side.

Brintellix 20 mg film-coated tablets

Red, almond-shaped (5 x 8.4 mm) film-coated tablet engraved with “TL” on one side and “20” on theother side.

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

The starting and recommended dose of Brintellix is 10 mg vortioxetine once daily in adults less than65 years of age.

Depending on individual patient response, the dose may be increased to a maximum of 20 mgvortioxetine 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 forconsolidation of the antidepressive response.

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

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

Cytochrome P450 inhibitors

Depending on individual patient response, a lower dose of vortioxetine may be considered if a strong

CYP2D6 inhibitor (e.g. bupropion, quinidine, fluoxetine, paroxetine) is added to vortioxetinetreatment (see section 4.5).

Cytochrome P450 inducers

Depending on individual patient response, a dose adjustment of vortioxetine may be considered if abroad cytochrome P450 inducer (e.g., rifampicin, carbamazepine, phenytoin) is added to vortioxetinetreatment (see section 4.5).

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

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

Brintellix is for oral use.

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

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Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant use with nonselective monoamine oxidase inhibitors (MAOIs) or selective MAO-Ainhibitors (see section 4.5).

Use in paediatric population

Brintellix should not be used in children and adolescents aged 7 to 17 years with MDD becauseefficacy has not been demonstrated (see section 5.1). In general , the adverse reaction profile ofvortioxetine in children and adolescents was similar to that seen for adults except for a higherincidence of abdominal pain-related events, and a higher incidence of sucidal ideation in adolescentsspecifically, compared to adults (see section 4.8 and 5.1). In clinical studies in children andadolescents treated with antidepressants, suicide-related behaviour (suicide attempt and suicidalthoughts) and hostility (predominantly aggression, oppositional behaviour, anger) were morefrequently 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 notoccur during the first few weeks or more of treatment, patients should be closely monitored until suchimprovement occurs. It is general clinical experience that the risk of suicide may increase in the earlystages of recovery.

Patients with a history of suicide-related events or those exhibiting a significant degree of suicidalideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts orsuicide attempts, and should receive careful monitoring during treatment. A meta-analysis ofplacebo-controlled clinical studies of antidepressants in adult patients with psychiatric disordersshowed an increased risk of suicidal behaviour with antidepressants compared to placebo, in patientsless than 25 years old.

Close supervision of patients and in particular those at high risk should accompany treatmentespecially in early treatment and following dose changes. Patients (and caregivers of patients) shouldbe alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts andunusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Seizures are a potential risk with antidepressants. Therefore, vortioxetine should be introducedcautiously in patients who have a history of seizures or in patients with unstable epilepsy (see section4.5). Treatment should be discontinued in any patient who develops seizures or for whom there is anincrease in seizure frequency.

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

Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS), potentially life-threateningconditions, may occur with vortioxetine. The risk of SS or NMS is increased with concomitant use ofserotonergic-active substances (including opioids and triptans), medicinal products that impair themetabolism of serotonin (including MAOIs), antipsychotics, and other dopamine antagonists. Patientsshould be monitored for the emergence of signs and symptoms of SS or NMS (see sections 4.3 and4.5).

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Serotonin Syndrome symptoms include mental status changes (e.g., agitation, hallucinations, coma),autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscularaberrations (e.g., hyperreflexia, uncoordination) and/or gastrointestinal symptoms (e.g., nausea,vomiting, diarrhoea). If this occurs, treatment with vortioxetine should be discontinued immediatelyand symptomatic treatment should be initiated.

Mania/hypomania

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

Aggression/agitation

Patients treated with antidepressants, including vortioxetine, may also experience feelings ofaggression, anger, agitation and irritability. Patient’s condition and disease status should be closelymonitored. Patients (and caregivers of patients) should be alerted to seek medical advice, ifaggressive/agitated behaviour emerges or aggravates.

Bleeding abnormalities, such as ecchymoses, purpura and other haemorrhagic events, such asgastrointestinal or gynaecological bleeding, have been reported rarely with the use of antidepressantswith serotonergic effect, including vortioxetine. SSRIs/SNRIs may increase the risk of postpartumhaemorrhage, and this risk could potentially apply also to vortioxetine (see section 4.6). Caution isadvised 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 withknown bleeding tendencies/disorders.

Hyponatraemia

Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has beenreported rarely with the use of antidepressants with serotonergic effect (SSRIs, SNRIs). Cautionshould be exercised in patients at risk, such as the elderly, patients with cirrhosis of the liver orpatients concomitantly treated with medicinal products known to cause hyponatraemia.

Discontinuation of vortioxetine should be considered in patients with symptomatic hyponatraemia andappropriate medical intervention should be instituted.

Glaucoma

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

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 mgvortioxetine once daily (see sections 4.2, pct. 4.8 and 5.2).

Given that subjects with renal or hepatic impairment are vulnerable and given that the data on the useof Brintellix in these subpopulations are limited, caution should be exercised when treating thesepatients. (see section 4.2 and 5.2).

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Brintellix contains Sodium

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

Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by CYP2D6and to a minor extent CYP3A4/5 and CYP2C9 (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 withirreversible non-selective MAOIs. Vortioxetine must not be initiated for at least 14 days afterdiscontinuation of treatment with an irreversible non-selective MAOI. Vortioxetine must bediscontinued 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 asmoclobemide, is contraindicated (see section 4.3). If the combination proves necessary, the addedmedicinal product should be given with minimum dosage and under close clinical monitoring forserotonin sSyndrome (see section 4.4).

Reversible, non-selective MAOI (linezolid)

The combination of vortioxetine with a weak reversible and non-selective MAOI, such as theantibiotic linezolid, is contraindicated (see section 4.3). If the combination proves necessary, the addedmedicinal product should be given with minimum dosage and under close clinical monitoring forserotonin 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 asselegiline or rasagiline should be administered with caution. Close monitoring for serotonin syndromeis necessary if used concomitantly (see section 4.4).

Serotonergic medicinal products

Co-administration of medicinal products with serotonergic effect e.g.opioids (including tramadol) andtriptans (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’swort (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 whenconcomitantly using other medicinal products capable of lowering the seizure threshold [e.g.,antidepressants (tricyclics, SSRIs, SNRIs), neuroleptics (phenothiazines, thioxanthenes andbutyrophenones), mefloquine, bupropion, tramadol] (see section 4.4).

ECT (electroconvulsive therapy)

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

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The exposure to vortioxetine increased 2.3-fold for area under the curve (AUC) when vortioxetine10 mg/day was co-administered with bupropion (a strong CYP2D6 inhibitor 150 mg twice daily) for14 days in healthy subjects. Co-administration resulted in a higher incidence of adverse reactionswhen 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 inhibitor (e.g., bupropion, quinidine, fluoxetine, paroxetine) is added to vortioxetinetreatment (see section 4.2).

CYP3A4 inhibitors and CYP2C9, and CYP2C19 inhibitors

When vortioxetine was co-administered following 6 days of ketoconazole 400 mg/day (a CYP3A4/5and 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, invortioxetine AUC was observed. No dose adjustment is needed.

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

Interactions in CYP2D6 poor metabolisers

Co-administration of strong inhibitors of CYP3A4 (such as itraconazol, voriconazole, clarithromycin,telithromycin, nefazodone, conivaptan and many of the HIV protease inhibitors) and inhibitors of

CYP2C9 (such as fluconazole and amiodarone) to CYP2D6 poor metabolisers (see section 5.2) hasnot been investigated specifically, but it is anticipated that it will lead to a more marked increasedexposure of vortioxetine in these patients as compared to the moderate effect described above.

Depending on individual patient response, a lower dose of vortioxetine may be considered if a stronginhibitor of CYP3A4 or CYP2C9 is co-administered in CYP2D6 poor metabolisers.

Cytochrome P450 inducers

When a single dose of 20 mg vortioxetine was co-administered following 10 days of rifampicin600 mg/day (a broad inducer of CYP isozymes) in healthy subjects, a 72% decrease in AUC ofvortioxetine was observed. Depending on individual patient response, a dose adjustment may beconsidered if a broad cytochrome P450 inducer (e.g., rifampicin, carbamazepine, phenytoin) is addedto vortioxetine treatment (see section 4.2).

Alcohol

No effect on the pharmacokinetics of vortioxetine or ethanol and no significant impairment, relative toplacebo, in cognitive function were observed when vortioxetine in a single dose of 20 mg or 40 mgwas co-administered with a single dose of ethanol (0.6 g/kg) in healthy subjects. However, alcoholintake is not advisable during antidepressant treatment.

Acetylsalicylic acid

No effect of multiple doses of acetylsalicylic acid 150 mg/day on the multiple-dose pharmacokineticsof 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 dosesof warfarin in healthy subjects. Also, no significant inhibitory effect, relative to placebo, on plateletaggregation or pharmacokinetics of acetylsalicylic acid or salicylic acid was observed whenacetylsalicylic acid 150 mg/day was co-administered following multiple doses of vortioxetineadministration in healthy subjects. However, caution should be exercised when vortioxetine iscombined 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 attributableto a pharmacodynamic interaction (see section 4.4).

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Cytochrome P450 substrates

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

Following multiple doses of vortioxetine, no inhibitory effect was observed in healthy subjects for thecytochrome 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, incognitive function was observed for vortioxetine following co-administration with a single 10 mg doseof diazepam. No significant effects, relative to placebo, were observed in the levels of sex hormonesfollowing co-administration of vortioxetine with a combined oral contraceptive (ethinyl estradiol30 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 beenreports of enhanced effects when antidepressants with serotonergic effect have been given togetherwith lithium or tryptophan; therefore, concomitant use of vortioxetine with these medicinal productsshould be undertaken with caution.

Interference with urine drug screens

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

There are limited data from the use of vortioxetine in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

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

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

Brintellix should only be administered to pregnant women if the expected benefits outweigh thepotential risk to the foetus.

Observational data have provided evidence of an increased risk (less than 2-fold) of postpartumhaemorrhage following exposure to an SSRI or SNRI within the month prior to birth. Although nostudies have investigated an association between vortioxetine treatment and postpartum haemorrhage,there is a potential risk, taking into account the related mechanism of action (See section 4.4)

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

A risk to the breastfeeding 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 oftherapy for the woman.

Fertility studies in male and female rats showed no effect of vortioxetine on fertility, sperm quality ormating 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 notbeen observed so far.

Brintellix has no or negligible influence on the ability to drive and use machines. However, as adversereactions such as dizziness have been reported, patients should exercise caution when driving oroperating hazardous machinery, especially when starting treatment with vortioxetine or whenchanging the dose.

The most common adverse reaction was nausea.

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 oninformation from clinical trials and post-marketing experience.

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SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION

Immune system disorders Not known* Anaphylactic reaction

Endocrine disorders Not known * Hyperprolactinaemia, in some casesassociated with galactorrhoea

Metabolism and nutrition disorders Not known * Hyponatraemia

Psychiatric disorders Common Abnormal dreams

Not known * Insomnia

Not known * Agitation, aggression (see section 4.4)

Nervous system disorders Common Dizziness

Uncommon Tremor

Not known * Serotonin Syndrome,

Headache,

Akathisia,

Bruxism,

Trismus,

Restless leg syndrome

Eye disorders Uncommon Blurred vision

Rare Mydriasis (which may lead to acutenarrow angle glaucoma - see section4.4)

Vascular disorders Uncommon Flushing

Not known* Haemorrhage (including contusion,ecchymosis, epistaxis, gastrointestinalor vaginal bleeding)

Gastrointestinal disorders Very common Nausea

Common Diarrhoea,

Constipation,

Vomiting,

Dyspepsia

Skin and subcutaneous tissue disorders Common Pruritus, including pruritusgeneralised

Hyperhidrosis

Uncommon Night sweats

Not known* Angioedema,

Urticaria

General disorder and administration Not known* Discontinuation syndromesite conditions

* Based on post-marketing cases

Nausea

Nausea was usually mild or moderate and occurred within the first two weeks of treatment. Thereactions were usually transient and did not generally lead to cessation of therapy. Gastrointestinaladverse reactions, such as nausea, occurred more frequently in women than men.

For doses ≥10 mg vortioxetine once daily, the withdrawal rate from the studies was higher in patientsaged ≥65 years.

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

Sexual dysfunction

In clinical studies, sexual dysfunction was assessed using the Arizona Sexual Experience Scale(ASEX). Doses of 5 to 15 mg showed no difference to placebo. However, the 20 mg dose ofvortioxetine was associated with an increase in sexual dysfunction (TESD)(see section 5.1). In thepost-marketing setting cases of sexual dysfunction have also been reported with doses of vortioxetinebelow 20 mg.

Class effect

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

A total of 304 children aged 7 to 11 years and 308 adolescents aged 12 to 17 years with majordepressive disorder (MDD) were treated with vortioxetine in two double-blind, placebo-controlledstudies, respectively. In general, the adverse reaction profile of vortioxetine in children andadolescents was similar to that observed inadults except for a higher incidenceof 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 20mg/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-termuse 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 abruptcessation of vortioxetine treatment. There was no clinically relevant difference to placebo in theincidence or nature of the discontinuation symptoms after treatment with vortioxetine (see section5.1). Cases describing discontinuation symptoms have been reported in the post-marketing setting andhave 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 ofvortioxetine discontinuation.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V

Ingestion of vortioxetine in clinical trials in the dose range of 40 mg to 75 mg has caused anaggravation of the following adverse reactions: nausea, postural dizziness, diarrhoea, abdominaldiscomfort, generalised pruritus, somnolence and flushing.

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

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There is limited experience with vortioxetine overdoses above 80 mg. Following dosages several foldhigher 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 specialised environment is recommended.

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

The mechanism of action of vortioxetine is thought to be related to its direct modulation ofserotonergic receptor activity and inhibition of the serotonin (5-HT) transporter. Nonclinical dataindicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partialagonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter, leading to modulation ofneurotransmission in several systems, including predominantly the serotonin but probably also thenorepinephrine, dopamine, histamine, acetylcholine, GABA and glutamate systems. This multimodalactivity is considered responsible for the antidepressant and anxiolytic-like effects and theimprovement of cognitive function, learning and memory observed with vortioxetine in animalstudies. However, the precise contribution of the individual targets to the observed pharmacodynamicprofile 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-HTtransporter ligands (11C-MADAM or 11C-DASB) to quantify the 5-HT transporter occupancy in thebrain across different dose levels. The mean 5-HT transporter occupancy in the raphe nuclei wasapproximately 50% at 5 mg/day, 65% at 10 mg/day and increased to above 80% at 20 mg/day.

The efficacy and safety of vortioxetine have been studied in a clinical programme that included morethan 6,700 patients, of whom more than 3,700 were treated with vortioxetine in short-term(≤12 weeks) studies of major depressive disorder (MDD). Twelve double-blind, placebo controlled,6/8-week, fixed-dose studies have been conducted to investigate the short-term efficacy ofvortioxetine in MDD in adults (including the elderly). The efficacy of vortioxetine was demonstratedwith at least one dosage group across 9 of the 12 studies, showing at least a 2-point difference toplacebo in the Montgomery and Åsberg Depression Rating Scale (MADRS) or Hamilton Depression

Rating Scale 24-item (HAM-D24) total score. This was supported by clinical relevance asdemonstrated by the proportions of responders and remitters and the improvement in the Clinical

Global Impression - Global Improvement (CGI-I) score. The efficacy of vortioxetine increased withincreasing dose.

The effect in the individual studies was supported by the meta-analysis (MMRM) of the mean changefrom baseline in MADRS total score at Week 6/8 in the short-term, placebo-controlled studies inadults. In the meta-analysis, the overall mean difference to placebo across the studies was statisticallysignificant: -2.3 points (p = 0.007), -3.6 points (p <0.001), and -4.6 points (p <0.001) for the 5, 10, and20 mg/day doses, respectively; the 15 mg/day dose did not separate from placebo in the meta-analysis,but the mean difference to placebo was -2.6 points. The efficacy of vortioxetine is supported by thepooled responder analysis, in which the proportion of responders ranged from 46% to 49% forvortioxetine versus 34% for placebo (p <0.01; NRI analysis).

Furthermore, vortioxetine, in the dose range of 5-20 mg/day, demonstrated efficacy on the broad rangeof depressive symptoms (assessed by improvement in all MADRS single-item scores).

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The efficacy of vortioxetine 10 or 20 mg/day was further demonstrated in a 12-week, double-blind,flexible-dose comparative study versus agomelatine 25 or 50 mg/day in patients with MDD.

Vortioxetine was statistically significantly better than agomelatine as measured by improvement in the

MADRS total score and supported by the clinical relevance as demonstrated by the proportions ofresponders and remitters and improvement in the CGI-I.

Maintenance

The maintenance of antidepressant efficacy was demonstrated in a relapse-prevention study. Patientsin remission after an initial 12-week open-label treatment period with vortioxetine were randomised tovortioxetine 5 or 10 mg/day or placebo and observed for relapse during a double-blind period of atleast 24 weeks (24 to 64 weeks). Vortioxetine was superior (p=0.004) to placebo on the primaryoutcome measure, the time to relapse of MDD, with a hazard ratio of 2.0; that is, the risk of relapsewas two times higher in the placebo group than in the vortioxetine group.

In the 8-week, double-blind, placebo-controlled, fixed-dose study in elderly depressed patients (aged≥65 years, n=452, 156 of whom were on vortioxetine), vortioxetine 5 mg/day was superior to placeboas measured by improvement in the MADRS and HAM-D24 total scores. The effect seen withvortioxetine was a 4.7 point difference to placebo in MADRS total score at Week 8 (MMRManalysis).

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

In severely depressed patients (baseline MADRS total score ≥30) and in depressed patients with a highlevel of anxiety symptoms (baseline HAM-A total score ≥20) vortioxetine also demonstrated efficacyin the short-term studies in adults (the overall mean difference to placebo in MADRS total score at

Week 6/8 ranged from 2.8 to 7.3 points and from 3.6 to 7.3 points, respectively,(MMRM analysis)). Inthe dedicated study in elderly, vortioxetine was also effective in these patients.

The maintenance of antidepressant efficacy was also demonstrated in this patient population in thelong-term relapse prevention study.

Effects of vortioxetine on the Digit Symbol Substitution Test (DSST), the University of California San

Diego Performance-Based Skills Assessment (UPSA) (objective measures) and Perceived Deficits

Questionnaire (PDQ) and Cognitive and Physical Functioning Questionnaire CPFQ (subjectivemeasures) scores

The efficacy of vortioxetine (5-20 mg/day) in patients with MDD has been investigated in 2 adult and1 elderly short-term, placebo-controlled studies.

Vortioxetine had a statistically significant effect versus placebo on the Digit Symbol Substitution Test(DSST), ranging from Δ = 1.75 (p = 0.019) to 4.26 (p <0.0001) in the 2 studies in adults and Δ = 2.79(p = 0.023) in the study in the elderly. In the meta-analyses (ANCOVA, LOCF) of the mean changefrom baseline in DSST number of correct symbols in all 3 studies, vortioxetine separated from placebo(p<0.05) with a standardised effect size of 0.35. When adjusting for the change in MADRS the totalscore in the meta-analysis of the same studies showed that vortioxetine separated from placebo(p<0.05) with a standardised effect size of 0.24.

One study assessed the effect of vortioxetine on functional capacity using the University of California

San Diego Performance-Based Skills Assessment (UPSA). Vortioxetine separated from placebostatistically with results of 8.0 for vortioxetine versus 5.1 points for placebo (p=0.0003).

In one study, vortioxetine was superior to placebo on subjective measures, evaluated using the

Perceived Deficits Questionnaire with results of -14.6 for vortioxetine and -10.5 for placebo(p=0.002). Vortioxetine did not separate from placebo on subjective measures when evaluated usingthe Cognitive and Physical Functioning Questionnaire with results of -8.1 for vortioxetine versus -6.9for placebo (p=0.086).

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Tolerability and safety

The safety and tolerability of vortioxetine have been established in short- and long-term studies acrossthe 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 weresystematically evaluated after abrupt treatment cessation of vortioxetine. There was no clinicallyrelevant difference to placebo in the incidence or nature of the discontinuation symptoms after eithershort-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 clinicalshort- 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 scoreshowed no clinically relevant difference to placebo in symptoms of sexual dysfunction at the 5 to15 mg/day doses of vortioxetine. For the 20 mg/day dose, an increase in TESD was seen compared toplacebo (an incidence difference of 14.2%, 95% CI [1.4, 27.0]).

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 weekswith 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 hadstatistically 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 notsignificantly 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 bothtreatment groups.

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

No clinically significant changes were observed in hepatic or 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 atdoses up to 40 mg daily, no potential for the prolongation of the QTc interval was observed.

Two short-term, randomised, double-blind, placebo-controlled, fixed-dose (vortioxetine 10 mg/dayand 20 mg/day), active-referenced (fluoxetine), efficacy and safety studies have been conducted; onein children aged 7 to 11 years with MDD, and one in adolescents aged 12 to 17 years with MDD. Thestudies included a 4-week single-blind placebo lead-in period with standardized psychosocialintervention (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 20mg/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 20mg/day), nor did the individual vortioxetine doses (10 and 20mg/day) show a nominally significantdifference from placebo. In general, the adverse event profile of vortioxetine in children was similar tothat 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 mostcommonly reported adverse events in the vortioxetine treatment groups were nausea, headache,vomiting, dizziness, and abdominal pain. The incidence of nausea, vomiting and abdominal pain washigher in the vortioxetine groups than in the placebo group. Suicidal ideation and behaviour werereported as adverse events during the 4-week single-blind lead-in period (placebo 2/677 [0.3%]), andduring the 8-week treatment period (vortioxetine 10 mg/day 1/149 [0.7%], placebo 1/153 [0.7%]). In

REG_00028683 v. 77.0addition, the event ‘non-specific active suicidal thoughts’ was reported in the C-SSRS in 5 patientsduring the 8-week treatment period (vortioxetine 20 mg/day 1/153 [0.7%], placebo 1/153 [0.7%] andfluoxetine 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 wasstatistically 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 placeboon the CDRS-R total score. In general, the adverse reaction profile of vortioxetine in adolescents wassimilar to that seen for adults except for higher incidences reported in adolescents than in adults forabdominal pain and suicidal ideation. Discontinuation due to adverse events (mostly due to suicidalideation, nausea and vomiting) was highest in patients treated with vortioxetine 20 mg/day (5.6%) ascompared to vortioxetine 10 mg/day (2.7%), fluoxetine (3.3%), and placebo (1.3%). The mostcommonly reported adverse events in the vortioxetine treatment groups were nausea, vomiting andheadache. Suicidal ideation and behaviour were reported as adverse events both during the 4-weeksingle-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 behaviour as measured by (C-SSRS) was similar acrosstreatment groups.

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

The European Medicines Agency has waived the obligation to submit the results of studies in majordepressive disorder with vortioxetine in children aged less than 7 years (see section 4.2 for informationon paediatric use).

Vortioxetine is slowly, but well absorbed after oral administration and the peak plasma concentrationis reached within 7 to 11 hours. Following multiple dosing of 5, 10, or 20 mg/day, mean Cmax values of9 to 33 ng/mL were observed. The absolute bioavailability is 75%. No effect of food on thepharmacokinetics was observed (see section 4.2).

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 beindependent of vortioxetine plasma concentrations.

Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by CYP2D6and to a minor extent CYP3A4/5 and CYP2C9, and subsequent glucuronic acid conjugation.

No inhibitory or inducing effect of vortioxetine was observed in the drug-drug interaction studies forthe CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1,or CYP3A4/5 (see section 4.5). Vortioxetine is a poor P-gp substrate and inhibitor.

The major metabolite of vortioxetine is pharmacologically inactive.

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

REG_00028683 v. 77.01/3 in the faeces. Only negligible amounts of vortioxetine are excreted in the faeces. Steady-stateplasma concentrations are achieved in approximately 2 weeks.

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 multipledoses of 5 to 20 mg/day.

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 of10 mg/day. The lowest effective dose of 5 mg vortioxetine once daily should always be used as thestarting dose in patients ≥ 65 years (see section 4.2). However, caution should be exercised whenprescribing to elderly patients at doses higher than 10 mg vortioxetine once daily (see section 4.4).

Following a single dose of 10 mg vortioxetine, renal impairment estimated using the Cockcroft-Gaultformula (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 fractionof vortioxetine was lost during dialysis (AUC and Cmax were 13% and 27% lower, respectively; 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).

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 AUCwere less than 10% lower in subjects with mild or moderate hepatic impairment, and 10% higher inthose with severe hepatic impairment. The changes in Cmax were less than 25% lower in all groups. Nodose adjustment is needed based on hepatic function (see section 4.2 and 4.4).

CYP2D6 gene types

The plasma concentration of vortioxetine was approximately two times higher in CYP2D6 poormetabolisers than in extensive metabolisers. Co-administration of strong CYP3A4/2C9 inhibitors to

CYP2D6 poor metabolisers could potentially result in higher exposure (see section 4.5).

In CYP2D6 ultra-rapid metabolisers, the plasma concentration of vortioxetine 10 mg/day werebetween those obtained in extensive metabolisers at 5 mg/day and 10 mg/day.

Depending on individual patient response, a dose adjustment may be considered (see section 4.2).

Pharmacokinetics of vortioxetine in paediatric patients with major depressive disorder following oraladministration of 5 to 20 mg once daily was characterized using population modeling analyses basedon 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 adultpatients.

Administration of vortioxetine in the general toxicity studies in mice, rats and dogs was mainlyassociated with CNS-related clinical signs. These included salivation (rat and dog), pupil dilatation(dog), and two incidences of convulsions in dogs in the general toxicity study programme. A no-effectlevel for convulsions was established with a corresponding safety margin of 5 considering themaximum recommended therapeutic dose of 20 mg/day. Target organ toxicity was restricted to

REG_00028683 v. 77.0kidneys (rats) and liver (mice and rats). The changes in the kidney in rats (glomerulonephritis, renaltubular obstruction, crystalline material in renal tubule) and in the liver of mice and rats(hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, crystalline material in bileducts) were seen at exposures more than 10-fold (mice) and 2-fold (rats) the human exposure at themaximum recommended therapeutic dose of 20 mg/day. These findings were mainly attributed torodent-specific vortioxetine-related crystalline material obstruction of the renal tubules and the bileducts, 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 notconsidered to pose a risk of carcinogenicity in humans.

Vortioxetine had no effect on rat fertility, mating performance, reproductive organs, or spermmorphology and motility. Vortioxetine was not teratogenic in rats or rabbits, but reproductive toxicityin terms of effects on foetal weight and delayed ossification were seen in the rat at exposures morethan 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 maternaltoxicity and with associated exposures similar to those achieved in humans following administrationof 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 withthose noted in adult animals.

Environmental risk assessment studies have shown that vortioxetine has the potential to be persistent,bioaccumulative and toxic to the environment (risk to fish). However, by recommended patient usagevortioxetine is considered to pose negligible risk to the aquatic and terrestrial environment (see section6.6).

Brintellix 5 mg film-coated tablets

Mannitol

Microcrystalline cellulose

Hydroxypropylcellulose

Sodium starch glycolate (type A)

Magnesium stearate

Hypromellose

Macrogol 400

Titanium dioxide (E171)

Iron oxide red (E172)

REG_00028683 v. 77.0

Brintellix 10 mg film-coated tablets

Mannitol

Microcrystalline cellulose

Hydroxypropylcellulose

Sodium starch glycolate (type A)

Magnesium stearate

Hypromellose

Macrogol 400

Titanium dioxide (E171)

Iron oxide yellow (E172)

Brintellix 15 mg film-coated tablets

Mannitol

Microcrystalline cellulose

Hydroxypropylcellulose

Sodium starch glycolate (type A)

Magnesium stearate

Hypromellose

Macrogol 400

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Brintellix 20 mg film-coated tablets

Mannitol

Microcrystalline cellulose

Hydroxypropylcellulose

Sodium starch glycolate (type A)

Magnesium stearate

Hypromellose

Macrogol 400

Titanium dioxide (E171)

Iron oxide red (E172)

Not applicable.

REG_00028683 v. 77.0

4 years.

This medicinal product does not require any special storage conditions.

Brintellix 5 mg film-coated tablets

Blister: Transparent; PVC/PVdC/aluminium blister.

Pack sizes of 14, 28 and 98 film-coated tablets.

Perforated unit dose blisters: PVC/PVdC/aluminium.

Pack sizes of 56 x 1 and 98 x 1 film-coated tablets.

Multipack containing 126 (9 x 14) and 490 (5 x (98x1)) film-coated tablets.

High-density polyethylene (HDPE) tablet container.

Pack sizes of 100 and 200 film-coated tablets.

Brintellix 10 mg film-coated tablets

Blister: Transparent; PVC/PVdC/aluminium blister.

Pack sizes of 7, 14, 28, 56 and 98 film-coated tablets.

Perforated unit dose blisters: PVC/PVdC/aluminium.

Pack sizes of 56 x 1 and 98 x 1 film-coated tablets.

Multipack containing 126 (9 x 14) and 490 (5 x (98x1)) film-coated tablets.

High-density polyethylene (HDPE) tablet container.

Pack sizes of 100 and 200 film-coated tablets.

Brintellix 15 mg film-coated tablets

Blister: Transparent; PVC/PVdC/aluminium blister.

Pack sizes of 14, 28, 56 and 98 film-coated tablets.

Perforated unit dose blisters: PVC/PVdC/aluminium.

Pack sizes of 56 x 1 and 98 x 1 film-coated tablets.

Multipack containing 490 (5 x (98x1)) film-coated tablets.

High-density polyethylene (HDPE) tablet container.

Pack sizes of 100 and 200 film-coated tablets.

Brintellix 20 mg film-coated tablets

Blister: Transparent; PVC/PVdC/aluminium blister.

Pack sizes of 14, 28, 56 and 98 film-coated tablets.

Perforated unit dose blisters: PVC/PVdC/aluminium.

Pack sizes of 56 x 1 and 98 x 1 film-coated tablets.

Multipack containing 126 (9 x 14) and 490 (5 x (98x1)) film-coated tablets.

High-density polyethylene (HDPE) tablet container.

Pack sizes of 100 and 200 film-coated tablets.

Not all pack sizes may be marketed.

REG_00028683 v. 77.0

This medicinal product may pose a risk to the environment (see section 5.3).

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

H. Lundbeck A/S

Ottiliavej 92500 Valby

Denmark

Brintellix 5 mg film-coated tablets

EU/1/13/891/001-007

EU/1/13/891/037-038

Brintellix 10 mg film-coated tablets

EU/1/13/891/008-017

EU/1/13/891/039

Brintellix 15 mg film-coated tablets

EU/1/13/891/018-026

Brintellix 20 mg film-coated tablets

EU/1/13/891/027-035

EU/1/13/891/040

Date of first authorisation: 18 December 2013

Date of latest renewal: 20 November 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.

REG_00028683 v. 77.0