Consumer medicine information

Brintellix

Vortioxetine

BRAND INFORMATION

Brand name

Brintellix

Active ingredient

Vortioxetine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Brintellix.

SUMMARY CMI

BRINTELLIX®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using Brintellix?

Brintellix contains the active ingredient vortioxetine. Brintellix is used to treat major depression in adults.

For more information, see Section 1. Why am I using Brintellix? in the full CMI.

2. What should I know before I use Brintellix?

Do not use if you have ever had an allergic reaction to vortioxetine or any of the ingredients listed at the end of the CMI.

Talk to your doctor or pharmacist if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Brintellix? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Brintellix and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Brintellix?

  • Follow all directions given to you by your doctor or pharmacist carefully.
  • Swallow the tablets whole with a full glass of water

More instructions can be found in Section 4. How do I use Brintellix? in the full CMI.

5. What should I know while using Brintellix?

Things you should do
  • Remind any doctor or dentist you visit that you are using Brintellix. If you become pregnant while being given this medicine, tell your doctor immediately.
Things you should not do
  • This medicine is prescribed to you by your doctor. Do not stop your treatment without talking to your doctor first
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how Brintellix affects you.
Drinking alcohol
  • Tell your doctor or pharmacist if you drink alcohol.
  • Avoid alcohol while you are taking Brintellix.
Looking after your medicine
  • Keep Brintellix in the blister pack until it is time to take them.
  • Keep Brintellix in a place where the temperature stays below 30°C.

For more information, see Section 5. What should I know while using Brintellix? in the full CMI.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Brintellix.

Brintellix helps most people with depression, but it may have unwanted side effects in some people.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

BRINTELLIX®

Active ingredient: Vortioxetine hydrobromide (vor-tee-ox-e-teen high-dro-bro-mide)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Brintellix. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Brintellix.

Where to find information in this leaflet:

1. Why am I using Brintellix?
2. What should I know before I use Brintellix?
3. What if I am taking other medicines?
4. How do I use Brintellix?
5. What should I know while using Brintellix?
6. Are there any side effects?
7. Product details

1. Why am I using Brintellix?

Brintellix contains the active ingredient vortioxetine. Brintellix is thought to work by its actions on multiple brain chemicals including serotonin, noradrenaline, dopamine, histamine and acetylcholine which are thought to be involved in controlling mood and related mental processes.

Brintellix is used to treat major depression in adults. Depression is longer lasting or more severe than the "low moods" everyone has from time to time due to the stress of everyday life. It is thought to be caused by a chemical imbalance in parts of the brain. This imbalance affects your whole body and can cause emotional, physical and cognitive symptoms such as feeling low in spirit, reduced ability to think or concentrate, or indecisiveness, loss of interest in activities, being unable to enjoy life, poor appetite or overeating, disturbed sleep, often waking up early, loss of sex drive, lack of energy and feeling guilty over nothing.

2. What should I know before I use Brintellix?

Warnings

Do not use Brintellix if:

  • you are allergic to vortioxetine, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take Brintellix at the same time as the following other medicines:

  • monoamine oxidase inhibitors (MAOIs), such as phenelzine, tranylcypromine, selegiline, rasagiline and moclobemide
  • medicines which act like a monoamine oxidase inhibitor, such as the antibiotic linezolid
Taking Brintellix with MAOIs may cause a serious reaction including sudden changes in mental state, twitching, rapid heartbeat, high blood pressure, fever and diarrhoea.
If you have taken an MAOI, you will need to wait at least 14 days before starting Brintellix. If you have used moclobemide, one day must elapse after you stop taking moclobemide before you start taking Brintellix.
After stopping Brintellix, you must allow at least 14 days before taking any MAOI or moclobemide.

Do not take Brintellix after the expiry date (EXP) printed on the pack. The expiry date refers to the last day of the month.

It may have no effect at all or, an entirely unexpected effect if you take it after the expiry date.

Do not take Brintellix if the packaging is torn or shows signs of having been tampered with.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Check with your doctor or pharmacist if you:

  • have any of the following medical conditions:
    - A tendency to bleed or bruise easily, or if you are pregnant, as there may be an increased risk of heavy vaginal bleeding shortly after birth, especially if you have a history of bleeding disorders.
    - Low sodium levels in the blood
    - Seizures or fits
    - A history of suicide-related events or suicidal ideas
    - A history, or family history, of mania or bipolar disorder (manic depression)
    - Other diseases affecting the brain, including psychiatric conditions
    - Other significant medical illnesses, such as unstable heart disease, stroke or severe liver or kidney disease
    - Glaucoma, risk of glaucoma, or any condition affecting the fluid pressure in the eye. If your eyes become painful and you develop blurred vision during treatment, contact your doctor
  • take any medicines for any other condition
  • When you are on antidepressant treatment, including vortioxetine, you may also experience feelings of aggression, agitation, anger and irritability. If this occurs, you should talk to your doctor.
  • Tell your doctor if you are 65 years of age or older.
  • Tell your doctor if you are receiving electroconvulsive therapy.
  • Do not give Brintellix to a child or adolescent.
  • Brintellix is not recommended in children or adolescents less than 18 years of age.
  • If you have not told your doctor about any of the above, tell them before you use Brintellix.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Brintellix should not be used during pregnancy unless the benefit outweighs the risk. Your doctor can discuss with you the risks and benefits involved. Brintellix may increase the risk of postpartum haemorrhage.

When taken during pregnancy, particularly in the last three months of pregnancy, medicines like Brintellix may increase the risk of a serious condition in babies called persistent pulmonary hypertension of the newborn (PPHN), making the baby breathe faster and appear bluish. These symptoms usually begin during the first 24 hours after the baby is born.

Other effects on your baby may include difficulty breathing, fits, body temperature changes, feeding difficulties, vomiting, stiff or floppy muscles, tremor, jitteriness, irritability, lethargy, constant crying, sleepiness or sleeping difficulties.

If your newborn baby has any of the above symptoms, you should contact your doctor immediately.

It is recommended that you do not breast-feed while taking Brintellix, as it may be excreted in the milk.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Brintellix and affect how it works. These include:

  • Monoamine oxidase inhibitors (MAOIs), including selegiline, rasagiline, linezolid and moclobemide.
You must stop taking MAOIs at least two weeks before starting Brintellix. You must wait at least one day after finishing moclobemide before you start Brintellix.
You must stop taking Brintellix at least two weeks before you start taking an MAOI or moclobemide.
  • rifampicin, an antibiotic
  • St. John's Wort, a herbal remedy
  • sumatriptan (and similar medicines ending in 'triptan'), medicines used to treat migraine headaches
  • lithium, used to treat mood swings and some types of depression
  • tryptophan, an amino acid
  • tramadol and other similar medicines (opioid based pain killers) used to relieve pain, these are known to increase the risk of a rare condition called serotonin syndrome
  • mefloquine, an anti-malaria medicine
  • bupropion, a medicine for nicotine dependence
  • medicines known to cause low sodium level in the blood
  • medicines used to thin the blood or known to prolong bleeding e.g. warfarin, dipyridamole, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs)
  • antipsychotics, a class of medicines used to treat mental illness, e.g. risperidone, olanzapine, quetiapine
  • tricyclic antidepressants, e.g. imipramine, desipramine
  • any other medicines for depression, anxiety, panic disorder, obsessive-compulsive disorder or pre-menstrual dysphoric disorder

These medicines may be affected by Brintellix, or may affect how well it works. You may need to use different amounts of medicines, or take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

If you have not told your doctor or pharmacist about any of these things, tell them before you take Brintellix.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Brintellix.

If you are having a urine drug screen, taking Brintellix may cause positive results for methadone when some test methods are used, even though you may not be taking methadone. If this happens, a more specific test can be performed.

4. How do I use Brintellix?

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

  • Your doctor will tell you how much Brintellix to take each day. Take the amount your doctor tells you to.
  • The usual dose for Brintellix in adults less than 65 years of age is 10 mg taken orally as one daily dose. The dose may be increased by your doctor to a maximum of 20 mg per day or lowered to a minimum of 5 mg per day.
  • For elderly people 65 years of age or older, the starting dose is 5 mg taken once daily.
  • Ask your doctor or pharmacist if you are unsure of the correct dose for you.
  • They will tell you exactly how much to take.
  • Follow the instructions they give you.
  • If you take the wrong dose, Brintellix may not work as well and your condition may not improve.

When to take Brintellix

  • Take Brintellix as a single dose either in the morning or in the evening.
  • Take your medicine at about the same time each day.
  • It does not matter if you take Brintellix before or after food.

How to take Brintellix

  • Swallow the tablets whole with a full glass of water.

How long to take it

Continue to take Brintellix even if it takes some time before you feel any improvement in your condition.

It may take two weeks, sometimes longer, before you feel any improvement.

Continue to take Brintellix for as long as your doctor recommends.

If your depression resolves while taking BRINTELLIX treatment should be continued for at least 6 months after you feel well again.

Your doctor will check your progress at regular intervals.

Do not change the dose or stop taking this medicine without first checking with your doctor.

If you forget to use Brintellix

Take the next dose at the usual time.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you use too much Brintellix

If you think that you have used too much Brintellix, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26 (Australia) or 0800 764 766 (New Zealand)), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Keep the telephone number handy.

Some of the signs of an overdose could be dizziness, feeling sick (nausea), diarrhoea, stomach discomfort, itching on the whole body, sleepiness and flushing.

Following intake of dosage several times higher than the prescribed dose, fits (seizures) and a rare condition called serotonin syndrome have been reported.

5. What should I know while using Brintellix?

Things you should do

Tell your doctor immediately if you become pregnant while taking Brintellix.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Brintellix.

Remind any doctor, dentist or pharmacist you visit that you are using Brintellix.

Keep all of your doctor's appointments so that your progress can be checked.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking Brintellix.

It may affect other medicines used during surgery.

If you have thoughts about killing yourself or other mental/mood changes, contact your doctor immediately or go to the nearest hospital for treatment.

All mentions of suicide or violence must be taken seriously.

Occasionally, the symptoms of depression may include thoughts of suicide or self-harm. It is possible that these symptoms continue or get worse until the full antidepressant effect of the medicine becomes apparent.

This is more likely to occur:

  • if you are a young adult, i.e. 18 to 24 years of age; or
  • you have previously had thoughts about killing or harming yourself

You may find it helpful to tell a relative or close friend that you are depressed and ask them to read this leaflet. You might ask them to tell you if they think your depression is getting worse, or if they are worried about changes in your behaviour.

Patients and care givers should pay attention for any of the following warning signs of suicide-related behaviour while taking Brintellix:

  • worsening of depression
  • thoughts or talk of death or suicide
  • thoughts or talk of self-harm or harm to others
  • any recent attempts of self-harm
  • increase in aggressive behaviour, irritability, agitation or any other unusual changes in behaviour or mood.

Things you should not do

Do not take Brintellix to treat any other complaints unless your doctor tells you to.

Do not give Brintellix to anyone else, even if they have the same condition as you.

Do not stop taking Brintellix, or lower the dosage, without checking with your doctor.

If you stop taking it suddenly, or reduce the amount you take, your condition may worsen.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Brintellix affects you.

Drinking alcohol

Tell your doctor or pharmacist if you drink alcohol.

Avoid alcohol while you are taking Brintellix.

Looking after your medicine

Follow the instructions in the carton on how to take care of your medicine properly.

Keep Brintellix in the blister pack until it is time to take them.

If you take the tablets out of the box or blister pack they may not keep well.

Store it in a cool dry place below 30°C away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above ground is a good place to store medicines.

Getting rid of any unwanted medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine you may have left over.

Do not use this medicine after the expiry date.

6. Are there any side effects?

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Brintellix.

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions.

Side effects are generally mild to moderate and occur within the first two weeks of treatment. They are usually temporary and generally do not require treatment cessation.

Less serious/common side effects

Less serious/common side effectsWhat to do
  • nausea
  • diarrhoea, constipation, vomiting
  • dizziness
  • itching of the whole body
Speak to your doctor or pharmacist if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • mania* (symptoms include mood of excitement, over-activity and uninhibited behaviour)
  • low sodium levels in the blood* (symptoms include feeling tired, weak and sick with weak muscles or feeling confused)
  • bleeding tendency* (e.g. bruising)
  • enlarged pupils (mydriasis), which can increase the risk of glaucoma*
  • agitation and aggression
Call your doctor straight away if you notice any of these serious side effects.
  • Thoughts of harming yourself or thoughts of suicide, see also section "Things you must do"*
  • serious allergic reaction
    (symptoms of an allergic reaction may include swelling of the face, lips, mouth or throat which may cause difficulty in swallowing or breathing, or rash, itching or hives)
  • high fever, agitation, confusion, trembling and abrupt contractions of muscles
    (these symptoms may be signs of a rare condition called serotonin syndrome)*
  • seizures*
  • bleeding* (e.g. vomiting of blood, traces of blood in your stools or your stools are dark in colour)
  • increased level of the hormone prolactin in the blood (hyperprolactinaemia)
  • excessive sweating
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

* The side effects marked with an asterisk (*) are a number of rare side effects that are known to occur with medicines that work in a similar way to Brintellix.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

7. Product details

What Brintellix contains

Active ingredient
(main ingredient)
  • Brintellix 5 mg tablets contain 5 mg vortioxetine (as hydrobromide) per tablet
  • Brintellix 10 mg tablets contain 10 mg vortioxetine (as hydrobromide) per tablet
  • Brintellix 15 mg tablets contain 15 mg vortioxetine (as hydrobromide) per tablet
  • Brintellix 20 mg tablets contain 20 mg vortioxetine (as hydrobromide) per tablet
Other ingredients
(inactive ingredients)
  • Mannitol
  • Microcrystalline cellulose
  • Hyprolose
  • Sodium starch glycollate type A
  • Magnesium stearate
  • Hypromellose
  • Titanium dioxide
  • Macrogol 400 Iron oxide red CI 77491 (5, 15 and 20 mg tablets)
  • Iron oxide yellow CI 77492 (10 and 15 mg tablets)
Potential allergensBrintellix does not contain lactose, gluten, sucrose, tartrazine or any other azo dyes.

Do not take this medicine if you are allergic to any of these ingredients.

What Brintellix looks like

  • Brintellix 5 mg tablets are pink, almond-shaped, biconvex film-coated tablet engraved with "TL" on one side and "5" on the other side.
  • Brintellix 10 mg tablets are yellow, almond-shaped, biconvex film-coated tablet engraved with "TL" on one side and "10" on the other side.
  • Brintellix 15 mg tablets are orange, almond-shaped, biconvex film-coated tablet engraved with "TL" on one side and "15" on the other side.
  • Brintellix 20 mg tablets are red, almond-shaped, biconvex film-coated tablet engraved with "TL" on one side and "20" on the other side.

Brintellix is available in blister packs of 28 tablets.

Australian Registration Numbers are:

5 mg tablet: AUST R 203986

10 mg tablet: AUST R 203955

15 mg tablet: AUST R 203981

20 mg tablet: AUST R 203970

New Zealand Registration Numbers are:

5 mg tablet: TT50-10588

10 mg tablet: TT50-10588a

15 mg tablet: TT50-10588b

20 mg tablet: TT50-10588c

Who distributes Brintellix

Brintellix is made by H. Lundbeck A/S, Denmark.

Distributed in Australia by:

Lundbeck Australia Pty Ltd
1 Innovation Road
North Ryde NSW 2113
Ph: 02 8669 1000

Distributed in New Zealand by:

Pharmacy Retailing t/a Healthcare Logistics
58 Richard Pearse Drive
Mangere, Auckland 2022
Ph: 0800 540 555

This leaflet was prepared in March 2022

Brintellix is a registered trademark of H. Lundbeck A/S.

Published by MIMS May 2022

BRAND INFORMATION

Brand name

Brintellix

Active ingredient

Vortioxetine

Schedule

S4

 

1 Name of Medicine

Vortioxetine hydrobromide.

2 Qualitative and Quantitative Composition

Each Brintellix tablet contains 6.355, 12.71, 19.065, or 25.42 mg of vortioxetine hydrobromide equivalent to 5, 10, 15, or 20 mg of vortioxetine, respectively.
Brintellix film-coated tablets contain mannitol, microcrystalline cellulose, hyprolose, sodium starch glycollate type A, magnesium stearate, hypromellose, titanium dioxide, macrogol 400, iron oxide red (5, 15 and 20 mg tablets) and iron oxide yellow (10 and 15 mg tablets). Brintellix does not contain lactose, gluten, sucrose, tartrazine or any other azo dyes.

3 Pharmaceutical Form

5 mg.

Pink, almond-shaped, biconvex film-coated tablet engraved with "TL" on one side and "5" on the other side.

10 mg.

Yellow, almond-shaped, biconvex film-coated tablet engraved with "TL" on one side and "10" on the other side.

15 mg.

Orange, almond-shaped, biconvex film-coated tablet engraved with "TL" on one side and "15" on the other side.

20 mg.

Red, almond-shaped biconvex film-coated tablet engraved with "TL" on one side and "20" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of major depressive disorder in adults including prevention of relapse.
Vortioxetine is not indicated for paediatric use.

4.2 Dose and Method of Administration

The starting and recommended dose of Brintellix in adults less than 65 years of age is 10 mg once daily, taken with or without food. Depending on individual patient response, the dose may be increased to a maximum of 20 mg daily or reduced to a minimum of 5 mg daily.
An antidepressant effect of Brintellix based on the primary efficacy measure was generally observed starting at week 2. If the depressive symptoms resolve, treatment for at least 6 months is recommended for consolidation of the antidepressive response.
Physicians should periodically re-evaluate the usefulness of the drug for individual patients.

Treatment discontinuation.

Patients being treated with Brintellix can abruptly stop taking Brintellix without the need for a gradual reduction in dose.

Missed dose.

If a dose is missed, the next dose should be taken at the usual time. Patients should not take a double dose to make up for a missed dose.

Special populations.

Elderly patients.

The recommended starting dose is 5 mg vortioxetine once daily and 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.

Patients with renal impairment.

No dose adjustment is recommended for patients with renal impairment or for patients with end-stage renal disease. However, as with any medicine, caution should be exercised when treating patients with severe renal insufficiency (see Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

No dose adjustment is recommended for patients with hepatic impairment; however, caution should be exercised when prescribing to these patients (see Section 5.2 Pharmacokinetic Properties).

Cytochrome P450 inhibitors.

Depending on individual patient response, a lower dose of Brintellix may be considered if strong CYP2D6 inhibitors (e.g. bupropion) are added to Brintellix treatment.

Cytochrome P450 inducers.

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

Paediatric population.

The safety and efficacy of vortioxetine in children aged 7-11 years have not been established. No data are available (see Section 4.4 Special Warnings and Precautions for Use). Brintellix should not be used in adolescents aged 12 to 17 years with MDD because efficacy has not been established (see Section 5.1 Pharmacodynamic Properties, Paediatric population). The safety of Brintellix in adolescent patients aged 12 to 17 years is described (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

4.3 Contraindications

Hypersensitivity to vortioxetine or any of the tablet excipients (see Section 2 Qualitative and Quantitative Composition).

Monoamine oxidase inhibitors (MAOIs).

Brintellix should not be used in combination with a MAOI, or within at least 14 days of discontinuing treatment with a MAOI. Brintellix should be discontinued for at least 14 days before starting treatment with a MAOI (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Clinical worsening and suicide risk.

The risk of suicide attempt is inherent in depression and may persist until significant remission occurs. This risk must be considered in all depressed patients.
Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored for clinical worsening and suicidality, especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient's presenting symptoms.
Patients (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms are present.
Patients with comorbid depression associated with other psychiatric disorders being treated with antidepressants should be similarly observed for clinical worsening and suicidality.
Patients with a history of suicide related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
Pooled analyses of 24 short-term (4 to 16-week), placebo-controlled studies of nine antidepressant medicines (SSRIs and others) in 4,400 children and adolescents with major depressive disorder (16 studies), obsessive-compulsive disorder (4 studies), or other psychiatric disorders (4 studies) have revealed a greater risk of adverse events representing suicidal behaviour or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients treated with an antidepressant was 4%, compared with 2% of patients given placebo. There was considerable variation in risk among the antidepressants, but there was a tendency towards an increase for almost all antidepressants studied. The risk of suicidality was most consistently observed in the major depressive disorder studies, but there were signals of risk arising from studies in other psychiatric indications (obsessive-compulsive disorder and social anxiety disorder) as well. No suicides occurred in these studies. It is unknown whether the suicidality risk in children and adolescent patients extends to use beyond several months.
The nine antidepressant medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) and four non-SSRIs (bupropion, mirtazapine, nefazodone, venlafaxine).
Pooled analyses of short-term studies of antidepressant medications have also shown an increased risk of suicidal thinking and behaviour, known as suicidality, in young adults aged 18 to 24 years during initial treatment (generally the first one to two months). Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond the age of 24 years, and there was a reduction with antidepressants compared to placebo in adults aged 65 years and older.
Symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adults, adolescents and children being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either worsening of depression and/or emergence of suicidal impulses has not been established, there is concern that such symptoms may be precursors of emerging suicidality.
Families and caregivers of children and adolescents being treated with antidepressants for major depressive disorder or for any other condition (psychiatric or non-psychiatric) should be informed about the need to monitor these patients for the emergence of agitation, irritability, unusual changes in behaviour, and other symptoms described above, as well as the emergence of suicidality, and to report such symptoms to healthcare providers immediately. It is particularly important that monitoring be undertaken during the initial few months of antidepressant treatment or at times of dose increase or decrease.
Prescriptions for Brintellix should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Serotonin syndrome/neuroleptic malignant syndrome (NMS).

Development of serotonin syndrome/NMS, potentially life-threatening conditions, may occur in association with treatment with serotonergic antidepressants, including vortioxetine. The risk of serotonin syndrome 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 serotonin syndrome or NMS (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Symptoms and signs of serotonin syndrome/NMS include rapid onset of neuromuscular excitation (hyperreflexia, incoordination, myoclonus, tremor), altered mental status (confusion, agitation, hypomania) and autonomic dysfunction (diaphoresis, diarrhoea, fever, shivering and rapidly fluctuating vital signs) and/or gastrointestinal symptoms (e.g. nausea, vomiting). Treatment with Brintellix should be discontinued if such events occur and supportive symptomatic treatment initiated.

Activation of mania/hypomania.

As with all drugs effective in the treatment of depression, 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. A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/manic episode in patients at risk of bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression.

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.

Seizures.

Seizures are a potential risk with antidepressant drugs. Therefore, as with other antidepressants, Brintellix should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Treatment should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency.

Haemorrhage.

As with any antidepressant with serotonergic effect, bleeding abnormalities, such as ecchymoses, purpura and gastrointestinal or gynaecological haemorrhage may occur. Antidepressants with serotonergic effects, including vortioxetine, may increase the risk of postpartum haemorrhage. 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, NSAIDs or aspirin) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions), and in patients with known bleeding tendencies.

Hyponatraemia.

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

Electroconvulsive therapy (ECT).

The safety and efficacy of the concurrent use of Brintellix and ECT have not been studied, and therefore, caution is advisable.

Use in patients with concomitant illness.

Brintellix has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease, patients with psychiatric co-morbidities, neurological co-morbidities, unstable medical illness or stroke. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.

Use in hepatic impairment.

Pharmacokinetic data in subjects with hepatic impairment are available (see Section 5.2 Pharmacokinetic Properties). No dose adjustment is needed based on hepatic function, however, caution should be exercised.

Use in renal impairment.

Limited data are available for patients with severe renal impairment. Caution should therefore be exercised (see Section 4.2 Dose and Method of Administration).

Angle-closure glaucoma.

Antidepressants including Brintellix may have an effect on pupil size resulting in mydriasis. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma, especially in pre-disposed patients. Brintellix should therefore be used with caution in patients with raised intraocular pressure and in those at risk of angle-closure glaucoma.

Use in the elderly.

The recommended starting dose is 5 mg vortioxetine once daily in patients ≥ 65 years of age (see Section 4.2 Dose and Method of Administration).

Paediatric use.

Brintellix is not indicated for use in patients below the age of 18 years. The safety and efficacy of Brintellix in children aged 7 to 11 years have not been established. Efficacy has not been demonstrated in adolescents aged 12 to 17 years with major depressive disorder (see Section 5.1 Pharmacodynamic Properties, Paediatric population). 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-related events and suicidal ideation (see Section 4.8 Adverse Effects (Undesirable Effects)). In clinical studies among children and adolescents treated with other antidepressants, suicide-related behaviour (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed compared to those treated with placebo.

Effects on laboratory tests.

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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Brintellix is extensively metabolised in the liver primarily through oxidation and subsequent glucuronic acid conjugation. In vitro studies indicate that the cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 are involved in the metabolism of vortioxetine (see Section 5.2 Pharmacokinetic Properties).

Potential for other medicinal products to affect Brintellix.

Irreversible non-selective MAOIs.

Due to the risk of serotonin syndrome, Brintellix is contraindicated in any combination with irreversible non-selective MAOIs. For patients changing treatment regimens, Brintellix must not be initiated for at least 14 days after discontinuation of treatment with an irreversible nonselective MAOI. Brintellix must be discontinued for at least 14 days before starting treatment with an irreversible non-selective MAOI (see Section 4.3 Contraindications).

Reversible, selective MAO-A inhibitor (moclobemide).

The combination of Brintellix with a reversible and selective MAO-A inhibitor (RIMA), such as moclobemide, is not recommended. A latent period of at least 24 hours after the last dose of moclobemide should be introduced before changing treatment to Brintellix. Moclobemide should not be used for at least 14 days after discontinuation of Brintellix (see Section 4.3 Contraindications).

Reversible, non-selective MAOI (linezolid).

The antibiotic linezolid is a weak reversible and non-selective MAOI and should not be given to patients treated with Brintellix. Linezolid should not be used for at least 14 days after discontinuation of Brintellix (see Section 4.3 Contraindications).

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

Although a lower risk of serotonin syndrome is expected with selective MAO-B inhibitors as compared with MAO-A inhibitors, the combination of Brintellix with selegiline or rasagiline should be exercised with caution. MAO-B inhibitors should not be used for at least 14 days after discontinuation of Brintellix (see Section 4.3 Contraindications).

Serotonergic medicinal products.

Co-administration with medicinal products that may affect the serotonergic neurotransmitter systems, such as serotonin reuptake inhibitors, lithium, St. John's Wort, dextromethorphan, opioids (including tramadol) and triptans (including sumatriptan) may lead to serotonin syndrome (see Section 4.4 Special Warnings and Precautions for Use).

St. John's wort.

Concomitant use of antidepressants with serotonergic effect and herbal remedies containing St. John's wort (Hypericum perforatum) may result in an increased incidence of adverse reactions including serotonin syndrome (see Section 4.4 Special Warnings and Precautions for Use).

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 and tramadol) (see Section 4.4 Special Warnings and Precautions for Use).

ECT (electroconvulsive therapy).

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

Cytochrome P450 inhibitors.

The exposure to vortioxetine increased 2.3-fold for AUC when Brintellix 10 mg/day was co-administered with bupropion (a strong CYP2D6 inhibitor) 150 mg b.i.d. for 14 days in 44 healthy subjects. The co-administration resulted in a higher incidence of adverse events when bupropion was added to Brintellix than when Brintellix was added to bupropion. Depending on individual patient response, a lower dose of Brintellix may be considered if strong CYP2D6 inhibitors (e.g. bupropion) are added to Brintellix treatment (see Section 4.2 Dose and Method of Administration).
When Brintellix was co-administered following 6 days of ketoconazole 400 mg/day (a CYP3A4/5 and P-glycoprotein inhibitor) in 17 healthy subjects, a 1.3-fold increase in vortioxetine AUC was observed. No dose adjustment is needed.
When Brintellix was co-administered following 6 days of fluconazole 200 mg/day (a CYP2C9, CYP2C19 and CYP3A4/5 inhibitor) in 16 healthy subjects, a 1.5-fold increase in AUC was observed. No dose adjustment is needed.

Cytochrome P450 inducers.

When a single dose of 20 mg Brintellix was co-administered following 10 days of rifampicin 600 mg/day (a broad inducer of CYP isozymes) in 14 healthy subjects, a 72% decrease in AUC of Brintellix was observed. Depending on individual patient response, a dose adjustment may be considered (see Section 4.2 Dose and Method of Administration).

Potential for Brintellix to affect other medicinal products.

Anticoagulants and antiplatelet agents.

No significant effects, relative to placebo, were observed in INR, prothrombin or plasma R-/S-warfarin values following co-administration of 10 mg/day vortioxetine for 14 days with stable doses of warfarin in 52 healthy subjects. Also, no significant inhibitory effect, relative to placebo, on platelet aggregation was observed when aspirin 150 mg/day was co-administered following 14 days of Brintellix 10 mg/day administration in 28 healthy subjects. However, as for other serotonergic agents, caution should be exercised when vortioxetine is combined with oral anticoagulants or antiplatelet agents due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction (see Section 4.4 Special Warnings and Precautions for Use).

Lithium, tryptophan.

No clinically relevant effect was observed during steady-state lithium exposure following co-administration with Brintellix 10 mg/day for 14 days in 16 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.

Alcohol.

Overall no impairment, relative to placebo, in cognitive function using a battery of neuropsychological tests was observed for Brintellix single doses of 20 and 40 mg following co-administration with a single dose of ethanol 0.6 g/kg in 55 healthy subjects.

Diazepam.

No significant impairment, relative to placebo, in cognitive function using a battery of neuropsychological tests was observed for vortioxetine following co-administration of Brintellix 10 mg/day with a single 10 mg dose of diazepam in 32 healthy subjects.

Oral contraceptives.

No significant effects, relative to placebo, were observed in the levels of sex hormones following co-administration of Brintellix 10 mg/day with a combined oral contraceptive (ethinylestradiol 30 microgram/levonorgestrel 150 microgram) in 25 healthy women for 21 days.

Cytochrome P450 substrates.

In vitro, vortioxetine did not show any relevant potential for inhibition or induction of cytochrome P450 isozymes.
No inhibitory effect of vortioxetine (10 mg/day for 14 days) was observed in healthy subjects for the cytochrome P450 isozymes CYP2C19 (omeprazole, diazepam), CYP2C9 (warfarin), CYP3A4/5 (ethinylestradiol), or CYP2B6 (bupropion). In a drug-drug interaction study in healthy subjects, no inhibitory effect of vortioxetine 10 mg/day for 14 days was observed for CYP2C9 (tolbutamide), CYP1A2 (caffeine), or CYP3A4/5 (midazolam), while CYP2D6 (dextromethorphan) was affected, the decrease in dextromethorphan levels was not considered clinically meaningful.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Vortioxetine given prior to and during mating, and in early pregnancy at oral doses achieving exposures 20 times the maximum recommended human dose had no effect on rat fertility, mating performance, or on sperm morphology and motility.
(Category B3)
Brintellix should not be used during pregnancy unless the benefit outweighs the risk. There are no or limited data (fewer than 300 pregnancy outcomes) from the use of vortioxetine in pregnant women.
In studies in which vortioxetine was administered to rats and rabbits during organogenesis, reduced foetal weight and delayed ossification was observed. In rats, these findings were observed at a vortioxetine exposure (plasma AUC) 30-fold or greater than that achieved at the maximum recommended human dose. No increased incidence of foetal malformations was noted. In rabbits, doses associated with delayed ossification, although resulting in vortioxetine exposures (plasma AUC) comparable to that at the maximum recommended human dose, were maternotoxic. In rabbits, an increased incidence of runts was observed at a vortioxetine exposure about 3-fold that at the maximum recommended human dose. A pre- and postnatal study in rats showed reduced pup survival during the lactation period at exposures (plasma AUC) 8-fold or greater than those achieved at the maximum recommended human dose.
The following symptoms may occur in newborns exposed to serotonergic agents 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 a majority of instances, such complications begin 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).
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 Special Warnings and Precautions for Use).
 In nonclinical studies vortioxetine related material was excreted in the milk of lactating rats.
It is expected that vortioxetine will be excreted into human milk. Consequently, breastfeeding is not recommended during treatment.

4.7 Effects on Ability to Drive and Use Machines

No significant impairment, relative to placebo, in driving performance, cognitive function or other psychomotor skills, was observed when 21 healthy subjects were administered single and multiple doses of 10 mg/day Brintellix. However, as with any psychoactive drug, patients should exercise caution when driving or operating hazardous machinery especially when starting treatment with Brintellix or when changing the dose.

4.8 Adverse Effects (Undesirable Effects)

Adverse events information for Brintellix was collected in patients with major depressive disorder (MDD) in a clinical programme that included more than 6,700 patients, of whom 3,460 were treated with Brintellix (5 to 20 mg/day) in short-term placebo controlled (up to 8 weeks) studies.
During clinical studies, all treatment groups were comparable with respect to gender, age and race. The mean age of patients was 46 years (18 to 88 years). Of these patients, approximately 67% were females and 33% were males.

Major depressive disorder (MDD) short-term studies in adults and elderly.

Adverse events that occurred in Brintellix treated patients in the course of the MDD short-term, placebo controlled studies with an incidence ≥ 10% were headache and nausea. The incidence of headache was 13.2% with Brintellix and 12.9% with placebo, which suggests that this is a non-specific symptom related to the underlying condition or treatment administration. The incidence of nausea was higher with Brintellix (24.1%) compared to the lower rates of nausea in the placebo group (8.1%). The majority of cases of nausea in the MDD short-term studies were transient and mild to moderate and did not generally lead to cessation of therapy. Gastrointestinal adverse reactions, such as nausea, occurred more frequently in women than men.
In the MDD short-term studies, discontinuation due to adverse events was more common with Brintellix (6.0%) compared with placebo (4.0%). Nausea was the most common reason for patients discontinuing due to adverse events.
Table 1 enumerates the incidence of treatment emergent adverse events that occurred in the short-term placebo-controlled studies. Events included are those occurring in 1% or more of patients treated with Brintellix (5 to 20 mg/day), and for which the incidence in patients treated with vortioxetine was greater than the incidence in placebo-treated patients.

Male and female sexual dysfunction.

Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be a consequence of pharmacologic treatment.
In the MDD 6 to 8-week placebo-controlled clinical studies with Brintellix, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms. These event terms have been aggregated and the incidence was 1.6% for Brintellix (5-20 mg; n = 3460) compared to 0.9% for placebo (n = 1968).
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), Table 2 shows the incidence of patients that developed treatment-emergent sexual dysfunction (TESD) when treated with Brintellix or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects.
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. See Figure 1.
In a 5-week, double-blind, placebo- and paroxetine-controlled study in healthy subjects with normal sexual functioning, without the confounding effect of depression, vortioxetine 10 mg/day (2.74 points, p=0.009) was statistically significantly better than paroxetine 20 mg/day as measured by change in the CSFQ-14 total score, whereas vortioxetine 20 mg/day was not (1.05 points, p=0.303). Neither vortioxetine 10 mg/day nor 20 mg/day were significantly worse than placebo. See Figure 2.

Insomnia.

Although insomnia is common in patients with depression, either as part of the disease or as an adverse effect of antidepressants, for vortioxetine, the reporting of adverse events related to insomnia and poor quality sleep is low and similar to placebo. Side effects related to insomnia or poor quality sleep may affect treatment adherence.
Table 3 shows the percentage of reported adverse reactions related to insomnia or poor sleep quality in the short-term studies in patients with MDD.

Discontinuation symptoms.

Brintellix was not associated with an increase in signs or symptoms consistent with withdrawal effects.

Weight.

Brintellix was not associated with weight gain (< 1 kg) in either short or long-term clinical studies.

Cardiovascular.

Brintellix was not associated with clinically significant effects on vital signs or the ECG. In a randomised, placebo- and positive-controlled, parallel group, thorough QTc study in 340 healthy subjects, treatment with Brintellix 10 or 40 mg/day for 14 days did not prolong the QTc interval.

Adverse events during treatment up to 64 weeks.

The adverse event profile of Brintellix in a longer-term study in patients with MDD consisting of a 24-64 week placebo-controlled relapse observation phase in remitters after a preceding 12-week acute treatment phase was similar to that observed in short-term studies.
During long-term, double-blind treatment the overall incidence of Treatment-Emergent Adverse Events (TEAEs) was 62% for Brintellix and 64% for placebo. Table 4 enumerates the incidence of TEAEs that occurred in 204 depressed patients who received Brintellix at 5 or 10 mg/day for 24 to 64 weeks. Events included are those occurring in 2% or more of patients treated with Brintellix, and for which the incidence in patients treated with Brintellix was greater than the incidence in placebo-treated patients.

Less common clinical study adverse drug reactions.

The events listed below present treatment emergent adverse events occurring in less than 1% of the patients treated with Brintellix (5 to 20 mg/day) in 12 short-term placebo controlled studies in depressed patients (n = 3460). The listing does not include events: 1) already listed in previous tables or elsewhere in labelling, 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.
The events are categorised by body system according to the following definitions: uncommon adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in less than 1/1000 patients.

Ear and labyrinth disorders.

Uncommon: vertigo.

Eye disorders.

Uncommon: dry eye.
Rare: mydriasis (which may lead to acute narrow angle glaucoma - see Section 4.4).

Gastrointestinal disorders.

Uncommon: abdominal distension, gastritis, epigastric discomfort, salivary hypersecretion.

General disorders and administration site conditions.

Uncommon: chest discomfort, malaise.

Investigations.

Uncommon: weight increased, electrocardiogram QT prolonged, heart rate increased, low density lipoprotein increased, blood cholesterol increased, blood triglycerides increased.

Nervous system.

Uncommon: dysgeusia, lethargy, tremor, myoclonus, formication.

Psychiatric disorders.

Uncommon: tension, bruxism, abnormal dreams, restlessness, derealisation.

Renal and urinary disorders.

Uncommon: micturition urgency, nocturia.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus, night sweats, rash.

Vascular disorders.

Uncommon: flushing, hypotension.

Post-market adverse drug reactions.

The following adverse events have been identified during post-approval use of Brintellix. These events are reported voluntarily from a population of uncertain size.

Nervous system disorders.

Serotonin syndrome, headache.

Skin and subcutaneous tissue disorders.

Angioedema, urticaria, rash, hyperhidrosis.

Immune system disorders.

Anaphylactic reaction.

Endocrine disorders.

Hyperprolactinemia.

Vascular disorders.

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

Metabolism and nutrition disorders.

Hyponatraemia.

Psychiatric disorders.

Agitation, aggression.

Paediatric population.

A total of 308 adolescent patients aged 12 to 17 years with major depressive disorder (MDD) were treated with vortioxetine in a double-blind, placebo-controlled study. 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-related events 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 behaviour 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 behaviour as measured by Columbia-Suicide Severity Rating Scale (C-SSRS) was similar across treatment groups.
Brintellix is not indicated for use in patients below the age of 18 years.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

In clinical studies no patients ingested more than 75 mg vortioxetine on a single occasion. The clinical studies included subjects who were administered 40 to 75 mg. Ingestion of vortioxetine in this dose range caused an aggravation of the following adverse events: nausea, postural dizziness, diarrhoea, 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 treatment of clinical symptoms and relevant monitoring. Medical follow-up in a specialised environment is recommended.
For information on the management of overdose, contact the Poison Information Centre (Tel: 13 11 26 for Australia and Tel: 0800 764 766 for New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The mechanism of action of vortioxetine is thought to be related to its multimodal activity, which is a combination of two pharmacological modes of action: direct modulation of receptor activity and inhibition of the serotonin transporter. In vitro studies 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 (5-HTT).
The precise contribution of the individual targets to the observed pharmacodynamic profile remains unclear. However, data from nonclinical serotonergic receptor and transporter occupancy studies coupled with neuronal firing and microdialysis studies suggest that the targets interact in a complex fashion, leading to modulation of neurotransmission in several systems, including serotonin, norepinephrine, dopamine, histamine, acetylcholine, gamma-aminobutyric acid (GABA) and glutamate systems within the forebrain. These multimodal pharmacological actions are thought to be responsible for the antidepressant effects of vortioxetine.

Pharmacodynamics.

Vortioxetine shows antidepressant and anxiolytic-like effects in some animal models (e.g. forced swim, conditioned fear-induced vocalisation, social interaction, marble burying and novelty-induced suppression of feeding tests). It is also effective in the models tested that are predictive of an enhanced effect on cognitive function (learning and memory) (e.g. contextual fear conditioning test and restoration of performance deficits induced by 5-HT depletion in the novel object recognition and Y-maze spontaneous alternation tests). In addition, in a sexual behavioural study in male rats at an oral dose achieving a vortioxetine plasma exposure similar to that at the maximum recommended human dose, vortioxetine did not induce sexual dysfunction.
In humans, two positron emission tomography (PET) studies have been performed using 5-HTT 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 trials.

Major depressive disorder (MDD) short-term studies in adults including elderly. The efficacy and safety of Brintellix have been studied in a clinical program that included more than 6,700 patients, of whom more than 3,700 were treated with Brintellix 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 Brintellix in MDD both in adults and in the elderly. The efficacy of Brintellix was demonstrated across 9 of the 12 studies, as measured by improvement in the Montgomery and Asberg 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.
In each of the 8 short-term studies in adults that demonstrated statistical superiority the effect seen with Brintellix ranged from 2.4 to 7.2 points difference to placebo in MADRS total score at week 6/8 mixed model repeated measures (MMRM) analysis. The antidepressant effect in the individual studies was supported by the meta-analysis using MMRM of the mean change from baseline in MADRS total score at week 6/8 in the short-term, placebo controlled studies in adults. In the meta-analysis, the overall mean difference to placebo across the studies was statistically significant: -2.3 points (p = 0.007), -3.6 points (p < 0.001), and -4.6 points (p < 0.001) for the 5, 10, and 20 mg/day doses, respectively; the 15 mg/day dose did not separate statistically from placebo in the meta-analysis, but the mean difference to placebo was -2.6 points. The efficacy of Brintellix increased with increasing dose.
The efficacy of Brintellix is supported by the pooled responder analysis, in which the proportion of responders ranged from 46% to 49% for vortioxetine versus 34% for placebo (p < 0.01; NRI analysis).
Furthermore Brintellix, 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).
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 one therapy with SSRI/SNRI for the current episode, Brintellix 10-20 mg/day was statistically significantly better (p = 0.002) than agomelatine 25-50 mg/day as measured by improvement in the MADRS total score.
In a short-term study, in adults, Brintellix (10 and 20 mg/day) was superior to placebo (p < 0.001) on the primary outcome measure, a composite cognition score consisting of two neuropsychological tests: a neuropsychological test of executive function, processing speed, and attention, the Digit Symbol Substitution Test (DSST) and a test of learning and memory, the Rey Auditory Verbal Learning Test (RAVLT).
MDD long-term relapse prevention. 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 Brintellix were randomised to Brintellix 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). A total of 639 patients were treated with open-label Brintellix. Four hundred (62.6%) patients achieved remission and entered the double-blind treatment phase. Remission was defined as MADRS total score ≤ 10. Relapse was defined as a MADRS total score ≥ 22 or lack of efficacy, as judged by the investigator.
Brintellix 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 Brintellix group.
Relapse rates during the first 24 weeks of the double blind period were 13.2% in the combined 5 mg and 10 mg Brintellix groups and 26.0% in the placebo group. See Figure 3.
Other clinical efficacy results.

Elderly.

In the double-blind, placebo-controlled, 8-week, fixed dose study in elderly (≥ 65 years) depressed patients, Brintellix 5 mg/day was statistically significantly superior to placebo (p = 0.001) as measured by improvement in the HAM-D24 and MADRS total scores.

Patients with severe depression or high levels of anxiety symptoms.

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) Brintellix also demonstrated efficacy in the short-term studies in adults (effect size ranged from 2.8 to 7.3 and from 3.6 to 7.3 points difference, respectively, to placebo in MADRS total score at week 6/8 (MMRM analysis)). In the dedicated study in elderly Brintellix was also effective in these patients. The maintenance of antidepressant efficacy was also demonstrated in this patient population in the long-term relapse prevention study.
The comparison of vortioxetine and escitalopram on antidepressant effects. In an 8-week, double-blind, flexible-dose, comparative study (n=424) of vortioxetine 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, patients in both treatment groups had similar maintenance of antidepressant effect.

Paediatric population.

One randomised, double-blind, placebo-controlled, active-referenced, fixed dose, 8-week study was conducted in adolescent patients with MDD aged 12 to 17 years. The study included a 4-week single-blind placebo lead-in period with standardized psychosocial intervention (N=777); only non-responders from the lead-in period were randomised (N=615). 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-related event and suicidal ideation (see Section 4.8 Adverse Effects (Undesirable Effects)).
Brintellix is not indicated for use in patients below the age of 18 years.

5.2 Pharmacokinetic Properties

Absorption.

The maximal plasma vortioxetine concentration (Cmax) after multiple oral doses is reached within 7 to 8 hours post-dose (Tmax). Steady-state mean Cmax values were 9, 18, and 33 nanogram/mL following doses of 5, 10, and 20 mg/day. The absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed.

Distribution.

The mean volume of distribution (Vss) from population PK analysis in healthy volunteers 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.

Metabolism.

Vortioxetine is extensively metabolised in the liver, primarily through oxidation and subsequent glucuronic acid conjugation. In vitro studies indicate that 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, or CYP3A4/5 nor was an inhibitory effect observed in vitro for CYP2D6 or CYP2E1. Vortioxetine is a poor P-gp substrate and inhibitor.
The major metabolite of vortioxetine (Lu AA34443) is pharmacologically inactive.

Excretion.

The mean elimination half-life and oral clearance from population PK analysis in healthy volunteers 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/nonlinearity.

The pharmacokinetics is linear and time independent in the dose range studied.

Pharmacokinetic/pharmacodynamic relationship(s).

There is a curve-linear concentration-response relationship between the plasma concentrations of vortioxetine after single and multiple doses of 2.5 to 60 mg/day and the occupancy of the 5-HT transporter in the brain, as measured using PET.

Special populations.

Elderly patients.

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. The recommended starting dose is 5 mg vortioxetine once daily in patients ≥ 65 years of age (see Section 4.2 Dose and Method of Administration).

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 11%), compared to healthy matched controls. In patients with end-stage renal disease, only a small fraction of vortioxetine was lost during the dialysis process (AUC and Cmax were 13% and 27% lower; n = 8) following a single 10 mg dose of vortioxetine. No dose adjustment is needed on the basis of renal function, however, caution should be exercised (see Section 4.4 Special Warnings and Precautions for Use).

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. After a single dose of 10 or 5 mg, the changes in AUC were less than 10% in subjects with mild or moderate hepatic impairment. Following a single dose of 5 mg, AUC was 44% higher and Cmax was 24% lower in those with severe hepatic impairment. No dose adjustment is needed on the basis of hepatic function, however caution should be exercised (see Section 4.4 Special Warnings and Precautions for Use).

CYP2D6 poor metabolisers.

The plasma concentration of vortioxetine was approximately two times higher in CYP2D6 poor metabolisers than in extensive metabolisers. No dose adjustment is needed (see Section 4.2 Dose and Method of Administration).

Gender.

Systemic exposures are similar between males and females of comparable body size and no dose adjustment is needed.

Race.

No dose adjustment on the basis of race or ethnicity is needed based on the population PK study. Race or ethnicity had no apparent effect on the pharmacokinetics of vortioxetine.

Paediatric 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 an efficacy and safety study (12-17 years). The pharmacokinetics of vortioxetine in paediatric patients was similar to that observed in adult patients.

5.3 Preclinical Safety Data

Genotoxicity.

Vortioxetine was not genotoxic in a bacterial reverse mutation assay and a chromosome aberration assay in human lymphocytes in vitro and an in vivo micronucleus test.

Carcinogenicity.

Two-year carcinogenicity studies were conducted with vortioxetine in mice and rats at doses which achieved exposures (plasma Cmax) well in excess of that at the maximum recommended human dose. Although there were some positive findings (increased incidences of hepatocellular adenomas in rats and in male mice, and of haemangiomas in the mesenteric lymph node and of histiocytic sarcomas in male rats, and of polypoid adenomas in the rectum of female rats). None of these findings were considered to pose a risk of carcinogenicity in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Blister packs: Transparent; PVC/PVdC/aluminium blister.
Pack sizes of 7 (10 mg only) and 28 film-coated tablets (all strengths).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

The drug substance is a white to very slightly beige powder. The molecule is not chiral.
Vortioxetine hydrobromide is slightly soluble in water; at ambient temperature solubility is equivalent to approximately 1.3 mg base/mL, pH being 5.5 in the saturated solution. At pH=7.4 the solubility is equivalent to approximately 50 microgram base/mL.
Dissociation Constant: pKa = 9.1 (± 0.1) and 3.0 (± 0.2).
Chemical name: 1-{2-[(2,4-dimethylphenyl) sulfanyl] phenyl}piperazine monohydrobromide.
Molecular formula: C18H22N2S, HBr.
Molecular mass: The relative molar mass of vortioxetine base is 298.45.
The relative molar mass of vortioxetine hydrobromide is 379.36.

Chemical structure.


CAS number.

508233-74-7 (vortioxetine base).
960203-27-4 (vortioxetine hydrobromide).

7 Medicine Schedule (Poisons Standard)

S4 - Prescription only medicine.

Summary Table of Changes