4.1. Therapeutic indications

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

4.2. Posology and method of administration

Posology

The starting and recommended dose of Brintellix is 10 mg vortioxetine once daily in adults less than 65 years of age.

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 populations

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

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 vortioxetine treatment (see section 4.5).

Cytochrome P450 inducers

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

Paediatric population

Brintellix should not be used in paediatric 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 paediatric 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.

4.3. Contraindications

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-A inhibitors (see section 4.5).

4.4. Special warnings and precautions for use

Use in paediatric 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 behaviour (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour, 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 behaviour 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 behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

Seizures

Seizures are a potential risk with antidepressants. Therefore, vortioxetine 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)

Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS), potentially life-threatening conditions, may occur with vortioxetine. The risk of SS or NMS is increased with concomitant use of serotonergic-active substances (including opioids and triptans), medicinal products that impair the metabolism of serotonin (including MAOIs), antipsychotics, and other dopamine antagonists. Patients should be monitored for the emergence of signs and symptoms of SS or NMS (see sections 4.3 and 4.5).

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

Mania/hypomania

Vortioxetine 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 aggression, 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 aggressive/agitated behaviour emerges or aggravates.

Haemorrhage

Bleeding abnormalities, such as ecchymoses, purpura and other haemorrhagic 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 haemorrhage, 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 medicinal products known to cause hyponatraemia.

Discontinuation of vortioxetine 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 (see sections 4.2, 4.8 and 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. (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'.

4.5. Interaction with other medicinal products and other forms of interaction

Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by CYP2D6 and 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 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 sSyndrome (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 administered 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), mefloquine, 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.

CYP2D6 inhibitors

The exposure to vortioxetine increased 2.3-fold for area under the 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 inhibitor (e.g., bupropion, quinidine, fluoxetine, paroxetine) is added to vortioxetine treatment (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 CYP3A4/5 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.

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) has not been investigated specifically, but it is anticipated that it will lead to a more marked increased exposure 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 strong inhibitor 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 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

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

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, 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).

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 a 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

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 medicinal product in the 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).

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

Observational data have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage 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 haemorrhage, 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 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 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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most common adverse reaction was nausea.

Tabulated list of adverse reactions

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.

SYSTEM ORGAN CLASS

FREQUENCY

ADVERSE REACTION

Immune system disorders

Not known*

Anaphylactic reaction

Endocrine disorders

Not known *

Hyperprolactinaemia, in some cases associated with galactorrhoea

Metabolism and nutrition disorders

Not known *

Hyponatraemia

Psychiatric disorders

Common

Abnormal dreams

Uncommon

Hallucinations

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 acute narrow angle glaucoma - see section 4.4)

Vascular disorders

Uncommon

Flushing

Not known*

Haemorrhage (including contusion, ecchymosis, epistaxis, gastrointestinal or vaginal bleeding)

Gastrointestinal disorders

Very common

Nausea

Common

Diarrhoea,

Constipation,

Vomiting,

Dyspepsia

Skin and subcutaneous tissue disorders

Common

Pruritus, including pruritus generalised Hyperhidrosis

Uncommon

Night sweats

Not known*

Angioedema,

Urticaria

Rash

Reproductive system and breast disorders

Not known*

Sexual dysfunction

General disorder and administration site conditions

Not known*

Discontinuation syndrome

* Based on post-marketing cases

Description of selected adverse reactions

Nausea

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

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

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 of vortioxetine was associated with an increase in sexual dysfunction (TESD)(see section 5.1). 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 medicinal product 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.

Paediatric 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 authorisation 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Ingestion of vortioxetine in clinical trials in the dose range of 40 mg to 75 mg has caused an aggravation of the following adverse reactions: nausea, postural dizziness, diarrhoea, abdominal discomfort, generalised 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 specialised environment is recommended.