Anx 130215 en

ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1
This medicinal product is subject to additional monitoring. This will allow quick identification of
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
Brintellix 5 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains vortioxetine hydrobromide equivalent to 5 mg vortioxetine.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet.
Pink, almond-shaped (5 x 8.4 mm) film-coated tablet engraved with “TL” on one side and “5” on the
other side.
4. CLINICAL PARTICULARS
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
Patients treated with Brintellix can abruptly stop taking the medicinal product without the need for a
gradual reduction in dose (see section 5.1).
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).
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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 Brintellix 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 Brintellix
treatment (see section 4.5).
Paediatric population
The safety and efficacy of Brintellix in children and adolescents aged less than 18 years have not been
established. No data are available (see section 4.4).
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 is not recommended for the treatment of depression in patients aged less than 18 years since
the safety and efficacy of vortioxetine have not been established in this age group (see section 4.2). In
clinical studies in children and adolescents treated with other 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.
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Seizures
Seizures are a potential risk with antidepressants. Therefore, Brintellix should be introduced cautiously
in patients who have a history of seizures or in patients with unstable epilepsy (see section 4.5).
Treatment should be discontinued in any patient who develops seizures or for whom there is an
increase in seizure frequency.
Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS)
Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS), potentially life-threatening

conditions, may occur with Brintellix. The risk of SS or NMS is increased with concomitant use of
serotonergic-active substances (including 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 Brintellix should be discontinued immediately and
symptomatic treatment should be initiated.
Mania/hypomania
Brintellix should be used with caution in patients with a history of mania/hypomania and should be
discontinued in any patient entering a manic phase.
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 (SSRIs, SNRIs). Caution is advised in patients taking anticoagulants and/or
medicinal products known to affect platelet function [e.g., atypical antipsychotics and phenothiazines,
most tricyclic antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid
(ASA)] (see section 4.5) and in patients with known bleeding tendencies/disorders.
Hyponatraemia
Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been
reported rarely with the use of antidepressants with serotonergic effect (SSRIs, SNRIs). Caution
should be exercised in patients at risk, such as the elderly, patients with cirrhosis of the liver or
patients concomitantly treated with medications known to cause hyponatraemia.
Discontinuation of Brintellix should be considered in patients with symptomatic hyponatraemia and
appropriate medical intervention should be instituted.
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 4.8 and 5.2).
Renal impairment
Limited data are available for patients with severe renal impairment. Caution should therefore be
exercised (see section 5.2).
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Hepatic impairment
Vortioxetine has not been studied in patients with severe hepatic impairment and caution should be
exercised when treating these patients (see section 5.2).
4.5 Interaction with other medicinal products and other forms of interaction
Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by

CYP2D6and to a minor extent CYP3A4/5and 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 Syndrome (see section 4.4).
Reversible, non-selective MAOI (linezolid)

The combination of vortioxetine with a weak reversible and non-selective MAOI, such as the
antibiotic linezolid, is contraindicated (see section 4.3). If the combination proves necessary, the added
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., tramadol, sumatriptan and
other triptans) 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
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.
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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
CYP3A4 inhibitors and CYP2C9 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.
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.
No inhibitory effect of 40 mg single-dose omeprazole (CYP2C19 inhibitor) was observed on the

multiple-dose pharmacokinetics of vortioxetine in healthy subjects.

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, as for other serotonergic medicinal products, caution
should be exercised when vortioxetine is combined with oral anticoagulants or antiplatelet medicinal
products due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction
(see section 4.4).
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Cytochrome P450 substrates
In vitro, vortioxetine did not show any relevant potential for inhibition or induction 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.
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 not be used during pregnancy unless the clinical condition of the woman requires
treatment with vortioxetine.
Breast-feeding
Available data in animals have shown excretion of vortioxetine/ vortioxetine metabolites in milk. It is
expected that vortioxetine will be excreted into human milk (see section 5.3).
A risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

Brintellix treatment taking into account the benefit of breast-feeding for the child and the benefit of
therapy for the woman.
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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, 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. Adverse reactions were 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.
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).
SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION

Metabolism and nutrition disorders Common Decreased appetite
Psychiatric disorders Common Abnormal dreams
Uncommon Bruxism
Nervous system disorders Common Dizziness
Unknown Serotonin Syndrome
Vascular disorders Uncommon Flushing
Gastrointestinal disorders Very common Nausea
Common Diarrhoea,
Constipation,
Vomiting
Skin and subcutaneous tissue disorders Common Generalised pruritus
Uncommon Night sweats
Description of selected adverse reactions
Elderly patients
For doses ≥10 mg vortioxetine once daily, the withdrawal rate from the studies was higher in patients
aged ≥65 years.
For doses of 20 mg vortioxetine once daily, the incidences of nausea and constipation were higher in
patients aged ≥65 years (42% and 15%, respectively) than in patients aged <65 years (27% and 4%,
respectively)(see section 4.4).
Sexual dysfunction
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
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vortioxetine was associated with an increase in treatment-emergent sexual dysfunction (TESD)(see
section 5.1) .
Class effect
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased
risk of bone fractures in patients receiving a drug from related pharmacological classes of
antidepressants (SSRIs or TCAs). The mechanism behind this risk is unknown, and it is not known if
this risk is also relevant for vortioxetine.
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 the national reporting system
listed in Appendix V
4.9 Overdose
There is limited experience with vortioxetine overdose.
Ingestion of vortioxetine in the dose range of 40 to 75 mg has caused an aggravation of the following
adverse reactions: nausea, postural dizziness, diarrhoea, abdominal discomfort, generalised pruritus,
somnolence and flushing.
Management of overdose should consist of treating clinical symptoms and relevant monitoring.
Medical follow-up in a specialised environment is recommended.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psychoanaleptics; Other antidepressants, ATC-code: N06AX26
Mechanism of action
The mechanism of action of vortioxetine is thought to be related to its direct modulation of

serotonergic receptor activity and inhibition of the serotonin (5-HT) transporter. Nonclinical data
indicate that vortioxetine is a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, 5-HT1B receptor partial
agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter, leading to modulation of
neurotransmission in several systems, including predominantly the serotonin but probably also the
norepinephrine, dopamine, histamine, acetylcholine, GABA and glutamate systems. This multimodal
activity is considered responsible for the antidepressant and anxiolytic-like effects and the
improvement of cognitive function, learning and memory observed with vortioxetine in animal
studies. However, the precise contribution of the individual targets to the observed pharmacodynamic
profile remains unclear and caution should be applied when extrapolating animal data directly to man.
In humans, two positron emission tomography (PET) studies have been conducted using 5-HT
transporter ligands (11C-MADAM or 11C-DASB) to quantify the 5-HT transporter occupancy in the
brain across different dose levels. The mean 5-HT transporter occupancy in the raphe nuclei was
approximately 50% at 5 mg/day, 65% at 10 mg/day and increased to above 80% at 20 mg/day.
Clinical efficacy and safety
The efficacy and safety of vortioxetine have been studied in a clinical programme that included more
than 6,700 patients, of whom more than 3,700 were treated with vortioxetine in short-term
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(≤12 weeks) studies of major depressive disorder (MDD). Twelve double-blind, placebo controlled,
6/8-week, fixed-dose studies have been conducted to investigate the short-term efficacy of
vortioxetine in MDD in adults (including the elderly). The efficacy of vortioxetine was demonstrated
with at least one dosage group across 9 of the 12 studies, showing at least a 2-point difference to
placebo in the Montgomery and Åsberg Depression Rating Scale (MADRS) or Hamilton Depression
Rating Scale 24-item (HAM-D24) total score. This was supported by clinical relevance as
demonstrated by the proportions of responders and remitters and the improvement in the Clinical
Global Impression – Global Improvement (CGI-I) score. The efficacy of vortioxetine increased with
increasing dose.
The effect in the individual studies was supported by the meta-analysis (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 from placebo in the meta-analysis,
but the mean difference to placebo was -2.6 points. The efficacy of vortioxetine 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, vortioxetine, in the dose range of 5-20 mg/day, demonstrated efficacy on the broad range
of depressive symptoms (assessed by improvement in all MADRS single–item scores).
The efficacy of vortioxetine 10 or 20 mg/day was further demonstrated in a 12-week, double-blind,

flexible-dose comparative study versus agomelatine 25 or 50 mg/day in patients with MDD.
Vortioxetine was statistically significantly better than agomelatine as measured by improvement in the
MADRS total score and supported by the clinical relevance as demonstrated by the proportions of
responders and remitters and improvement in the CGI-I.
Maintenance
The maintenance of antidepressant efficacy was demonstrated in a relapse-prevention study. Patients
in remission after an initial 12-week open-label treatment period with vortioxetine were randomised to
vortioxetine 5 or 10 mg/day or placebo and observed for relapse during a double-blind period of at
least 24 weeks (24 to 64 weeks). Vortioxetine was superior (p=0.004) to placebo on the primary
outcome measure, the time to relapse of MDD, with a hazard ratio of 2.0; that is, the risk of relapse
was two times higher in the placebo group than in the vortioxetine group.
Elderly
In the 8-week, double-blind, placebo-controlled, fixed-dose study in elderly depressed patients (aged
≥65 years, n=452, 156 of whom were on vortioxetine), vortioxetine 5 mg/day was superior to placebo
as measured by improvement in the MADRS and HAM-D24 total scores. The effect seen with
vortioxetine was a 4.7 point difference to placebo in MADRS total score at Week 8 (MMRM
analysis).
Patients with severe depression or with depression and high levels of anxiety symptoms
In severely depressed patients (baseline MADRS total score ≥30) and in depressed patients with a high
level of anxiety symptoms (baseline HAM-A total score ≥20) vortioxetine also demonstrated efficacy
in the short-term studies in adults (the overall mean difference to placebo in MADRS total score at
Week 6/8 ranged from 2.8 to 7.3 points and from 3.6 to 7.3 points, respectively,(MMRM analysis)). In
the dedicated study in elderly, vortioxetine 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.
Tolerability and safety

The safety and tolerability of vortioxetine have been established in short- and long-term studies across
the dose range of 5 to 20 mg/day. For information on undesirable effects, see section 4.8.
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Vortioxetine did not increase the incidence of insomnia or somnolence relative to placebo.
In clinical short- and long-term placebo-controlled studies, potential discontinuation symptoms were
systematically evaluated after abrupt treatment cessation of vortioxetine. There was no clinically
relevant difference to placebo in the incidence or nature of the discontinuation symptoms after either
short-term (6-12 weeks) or long-term (24-64 weeks) treatment with vortioxetine.
The incidence of self-reported adverse sexual reactions was low and similar to placebo in clinical
short- and long-term studies with vortioxetine. In studies using the Arizona Sexual Experience Scale
(ASEX), the incidence of treatment-emergent sexual dysfunction (TESD) and the ASEX total score
showed no clinically relevant difference to placebo in symptoms of sexual dysfunction at the 5 to
15 mg/day doses of vortioxetine. For the 20 mg/day dose, an increase in TESD was seen compared to
placebo (an incidence difference of 14.2%, 95% CI [1.4, 27.0]).
Vortioxetine had no effect relative to placebo on body weight, heart rate, or blood pressure in clinical
short- and long-term studies.
No clinically significant changes were observed in hepatic or renal assessments in clinical studies.
Vortioxetine has not shown any clinically significant effect on ECG parameters, including the QT,
QTc, PR and QRS intervals, in patients with MDD. In a thorough QTc study in healthy subjects at
doses up to 40 mg daily, no potential for the prolongation of the QTc interval was observed.
The European Medicines Agency has waived the obligation to submit the results of studies in major
depressive disorder with vortioxetine in children aged less than 7 years (see section 4.2 for information
on paediatric use).
The European Medicines Agency has deferred the obligation to submit the results of studies in major
depressive disorder with vortioxetine in children and adolescents aged 7 to 18 years (see section 4.2
for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Vortioxetine is slowly, but well absorbed after oral administration and the peak plasma concentration
is reached within 7 to 11 hours. Following multiple dosing of 5, 10, or 20 mg/day, mean Cmax values of
9 to 33 ng/mL were observed. The absolute bioavailability is 75%. No effect of food on the
pharmacokinetics was observed (see section 4.2).
Distribution
The mean volume of distribution (Vss) is 2,600 L, indicating extensive extravascular distribution.
Vortioxetine is highly bound to plasma proteins (98 to 99%) and the binding appears to be
independent of vortioxetine plasma concentrations.
Biotransformation
Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by CYP2D6
and to a minor extent CYP3A4/5 and CYP2C9, and subsequent glucuronic acid conjugation.
No inhibitory or inducing effect of vortioxetine was observed in the drug-drug interaction studies for
the CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1,
or CYP3A4/5 (see section 4.5). Vortioxetine is a poor P-gp substrate and inhibitor.
The major metabolite of vortioxetine is pharmacologically inactive.
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Elimination
The mean elimination half-life and oral clearance are 66 hours and 33 L/h, respectively.
Approximately 2/3 of the inactive vortioxetine metabolites are excreted in the urine and approximately
1/3 in the faeces. Only negligible amounts of vortioxetine are excreted in the faeces. Steady-state
plasma concentrations are achieved in approximately 2 weeks.
Linearity/non-linearity
The pharmacokinetics are linear and time independent in the dose range studied (2.5 to 60 mg/day).
In accordance with the half-life, the accumulation index is 5 to 6 based on AUC0-24h following multiple
doses of 5 to 20 mg/day.
Special populations
Elderly
In elderly healthy subjects (aged ≥65 years; n=20), the exposure to vortioxetine increased up to 27%
(Cmax and AUC) compared to young healthy control subjects (aged ≤45 years) after multiple doses of
10 mg/day. The lowest effective dose of 5 mg vortioxetine once daily should always be used as the
starting dose in patients ≥ 65 years (see section 4.2). However, caution should be exercised when
prescribing to elderly patients at doses higher than 10 mg vortioxetine once daily (see section 4.4).
Renal impairment
Following a single dose of 10 mg vortioxetine, renal impairment estimated using the Cockcroft-Gault
formula (mild, moderate, or severe; n=8 per group) caused modest exposure increases (up to 30%),
compared to healthy matched controls. In patients with end-stage renal disease, only a small fraction
of vortioxetine was lost during dialysis (AUC and Cmax were 13% and 27% lower, respectively; n=8)
following a single 10 mg dose of vortioxetine. No dose adjustment is needed (see section 4.4).
Hepatic impairment
Following a single dose of 10 mg vortioxetine, no impact of mild or moderate hepatic impairment
(Child-Pugh Criteria A or B; n=8 per group) was observed on the pharmacokinetics of vortioxetine
(changes in AUC were less than 10%). No dose adjustment is needed (see section 4.2). Vortioxetine
has not been studied in patients with severe hepatic impairment and caution should be exercised when
treating these patients (see section 4.4).
CYP2D6 gene types

The plasma concentration of vortioxetine was approximately two times higher in CYP2D6 poor
metabolisers than in extensive metabolisers. Co-administration of strong CYP3A4/2C9 inhibitors to
CYP2D6 poor metabolisers could potentially result in higher exposure (see section 4.5).
In CYP2D6 ultra-rapid metabolisers, the plasma concentration of vortioxetine 10 mg/day were

between those obtained in extensive metabolisers at 5 mg/day and 10 mg/day.
As for all patients, depending on individual patient response, a dose adjustment may be considered
(see section 4.2).
5.3 Preclinical safety data
Administration of vortioxetine in the general toxicity studies in mice, rats and dogs was mainly
associated with CNS-related clinical signs. These included salivation (rat and dog), pupil dilatation
(dog), and two incidences of convulsions in dogs in the general toxicity study programme. A no-effect
level for convulsions was established with a corresponding safety margin of 5 considering the
maximum recommended therapeutic dose of 20 mg/day. Target organ toxicity was restricted to
kidneys (rats) and liver (mice and rats). The changes in the kidney in rats (glomerulonephritis, renal
tubular obstruction, crystalline material in renal tubule) and in the liver of mice and rats
(hepatocellular hypertrophy, hepatocyte necrosis, bile duct hyperplasia, crystalline material in bile
12
ducts) were seen at exposures more than 10-fold (mice) and 2-fold (rats) the human exposure at the
maximum recommended therapeutic dose of 20 mg/day. These findings were mainly attributed to
rodent-specific vortioxetine-related crystalline material obstruction of the renal tubules and the bile
ducts, respectively, and considered of low risk to humans.
Vortioxetine was not genotoxic in a standard battery of in vitro and in vivo tests.
Based on results from conventional 2-year carcinogenicity studies in mice or rats, vortioxetine is not
considered to pose a risk of carcinogenicity in humans.
Vortioxetine had no effect on rat fertility, mating performance, reproductive organs, or sperm
morphology and motility. Vortioxetine was not teratogenic in rats or rabbits, but reproductive toxicity
in terms of effects on foetal weight and delayed ossification were seen in the rat at exposures more
than 10-fold the human exposure at the maximum recommended therapeutic dose of 20 mg/day.
Similar effects were seen in the rabbit at sub-therapeutic exposure.
In a pre- and post-natal study in rats, vortioxetine was associated with increased pup mortality,
reduced bodyweight gain, and delayed pup development at doses that did not result in maternal
toxicity and with associated exposures similar to those achieved in humans following administration
of vortioxetine 20 mg/day (see section 4.6).
Vortioxetine-related material was distributed to the milk of lactating rats (see section 4.6).
In juvenile toxicity studies in rats, all vortioxetine treatment-related findings were consistent with
those noted in adult animals.
The active ingredient vortioxetine hydrobromide is currently considered hazardous (persistent,

bioaccumulative and toxic; risk to fish) for the environment (for instruction on disposal see section
6.6).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core
Mannitol
Microcrystalline cellulose
Hydroxypropylcellulose
Sodium starch glycolate (type A)
Magnesium stearate
Tablet coating
Hypromellose
Macrogol 400
Titanium dioxide (E171)
Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
13
6.3 Shelf life
30 months.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
Blister: Transparent; PVC/PVdC/aluminium blister.

Pack sizes of 14, 28 and 98 film-coated tablets.
Perforated unit dose blisters: PVC/PVdC/aluminium.

Pack sizes of 56 x 1 and 98 x 1 film-coated tablets.
Multipack containing 126 (9 x 14) and 490 (5 x (98x1)) film-coated tablets.
High-density polyethylene (HDPE) tablet container.

Pack sizes of 100 and 200 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
7. MARKETING AUTHORISATION HOLDER
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/13/891/001
EU/1/13/891/002
EU/1/13/891/003
EU/1/13/891/004
EU/1/13/891/005
EU/1/13/891/006
EU/1/13/891/007
EU/1/13/891/037
EU/1/13/891/038
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 18 December 2013
14
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.
15
Film-coated tablet.
Yellow, almond-shaped (5 x 8.4 mm) film-coated tablet engraved with “TL” on one side and “10” on
the other side.
Posology
65 years of age.

Special populations
Elderly patients
16
CYP2D6 inhibitor (e.g., bupropion, quinidine, fluoxetine, paroxetine) is added to Brintellix treatment
(see section 4.5).

broad cytochrome P450 inducer (e.g. rifampicin, carbamazepine, phenytoin) is added to Brintellix

stages of recovery.
17
Seizures

Mania/hypomania
Haemorrhage
Hyponatraemia
Elderly
Renal impairment
18
Hepatic impairment
and to a minor extent CYP3A4/5 and CYP2C9 (see section 5.2).

(see section 4.3).




St. John’s wort



19
CYP2D6 inhibitors
CYP2D6 inhibitor (e.g. bupropion, quinidine, fluoxetine, paroxetine) is added to vortioxetine




Alcohol

(see section 4.4).
20

Lithium, tryptophan
Pregnancy
Breast-feeding

21
Fertility

Uncommon Bruxism
Common Diarrhoea,
Constipation,
Vomiting
Elderly patients
aged ≥65 years.
Sexual dysfunction
22
vortioxetine was associated with an increase in treatment-emergent sexual dysfunction (TESD)(see
section 5.1) .
Class effect
4.9 Overdose
Mechanism of action

23
(≤12 weeks) studies of major depressive disorder (MDD). Twelve double-blind, placebo-controlled,
increasing dose.
20 mg/day doses, respectively; the 15mg/day dose did not separate from placebo in the meta-analysis,
The efficacy of vortioxetine 10 or 20 mg/day was further demonstrated in a 12-week, double-blind,

flexible-dose comparative study versus agomelatine 25 or 50 mg/day in patients with MDD.
Vortioxetine was statistically significantly better than agomelatine as measured by improvement in the
MADRS total score and supported by the clinical relevance as demonstrated by the proportions of
responders and remitters and improvement in the CGI-I.
Maintenance
Elderly
analysis).
Week 6/8 ranged from 2.8 to 7.3 points and from 3.6 to 7.3 points, respectively, (MMRM analysis)).
In the dedicated study in elderly, vortioxetine was also effective in these patients.
24
on paediatric use).
Absorption
Distribution
Biotransformation
25
or CYP3A4/5. Vortioxetine is a poor P-gp substrate and inhibitor.
Elimination
Special populations
Elderly
starting dose in patients ≥ 65 years of age (see section 4.2). However, caution should be exercised
when prescribing to elderly patients at doses higher than 10 mg vortioxetine once daily (see section
4.4).
Renal impairment
Hepatic impairment
CYP2D6 gene types

(see section 4.2).
26

6.6).
Tablet core
Mannitol
Magnesium stearate
Tablet coating
Hypromellose
Macrogol 400
Iron oxide yellow (E172)
27
Not applicable.
6.3 Shelf life
30 months.
6.5 Nature and contents of

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

Multipack containing 126 (9 x 14) and 490 (5 x (98x1)) film-coated tablets.
High density polyethylene (HDPE) tablet container.

requirements.
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
EU/1/13/891/008
EU/1/13/891/009
EU/1/13/891/010
EU/1/13/891/011
EU/1/13/891/012
EU/1/13/891/013
EU/1/13/891/014
EU/1/13/891/015
EU/1/13/891/016
EU/1/13/891/017
EU/1/13/891/039
28
29

Film-coated tablet.
Orange, almond-shaped (5 x 8.4 mm) film-coated tablet engraved with “TL” on one side and “15” on
the other side.
Posology
65 years of age.

Special populations
Elderly patients
30
(see section 4.5).


stages of recovery.
31
Seizures

Mania/hypomania
Haemorrhage
Hyponatraemia
Elderly
Renal impairment
32
Hepatic impairment

(see section 4.3).




St. John’s wort



33
CYP2D6 inhibitors




Alcohol

(see section 4.4).
34
In vitro, vortioxetine did not show any relevant potential for inhibition or induction of cytochrome
P450 isozymes (see section 5.2).

Lithium, tryptophan
Pregnancy
Breast-feeding

35
Fertility

Uncommon Bruxism
Common Diarrhoea,
Constipation,
Vomiting
Elderly patients
aged ≥65 years.
Sexual dysfunction
36
vortioxetine was associated with an increase in treatment emergent sexual dysfunction (TESD)(see
section 5.1) .
Class effect
4.9 Overdose
Mechanism of action

37
increasing dose.
The efficacy of vortioxetine 10 or 20 mg/day was further demonstrated in a 12-week,

double-blind, flexible-dose comparative study versus agomelatine 25 or 50 mg/day in patients with
MDD. Vortioxetine was statistically significantly better than agomelatine as measured by
improvement in the MADRS total score and supported by the clinical relevance as demonstrated by
the proportions of responders and remitters and improvement in the CGI-I.
Maintenance
Elderly
analysis).
level of anxiety symptoms (baseline HAM-A total score ≥20), vortioxetine also demonstrated efficacy
Week 6/8 ranged from 2.8 to 7.3 points and from 3.6 to 7.3 points, respectively (MMRM analysis)). In
the dedicated study in elderly, vortioxetine was also effective in these patients.
long-term relapse-prevention study.

38
on paediatric use).
Absorption
Distribution
Biotransformation
39
Elimination
Special populations
Elderly
4.4).
Renal impairment
Hepatic impairment
CYP2D6 gene types

metabolisers than in extensive metabolisers. Co-administration of strong CYP3A4/2C9-inhibitors, to
(see section 4.2).
40

6.6).
Tablet core
Mannitol
Magnesium stearate
Tablet coating
Hypromellose
Macrogol 400
Iron oxide yellow (E172)
Not applicable.
41
6.3 Shelf life
30 months.

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

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

requirements.
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
EU/1/13/891/018
EU/1/13/891/019
EU/1/13/891/020
EU/1/13/891/021
EU/1/13/891/022
EU/1/13/891/023
EU/1/13/891/024
EU/1/13/891/025
EU/1/13/891/026
42
43
Each film-coated tablet contains vortioxetine hydrobromide equivalent to 20 mg vortioxetine-
Film-coated tablet.
Red, almond-shaped (5 x 8.4 mm) film-coated tablet engraved with “TL” on one side and “20” on the
other side.
Posology
65 years of age.

Special populations
Elderly patients
44
(see section 4.5).


stages of recovery.
45
Seizures

Mania/hypomania
Haemorrhage
medicinal products known to affect platelet function [e.g. atypical antipsychotics and phenothiazines,
Hyponatraemia
Elderly
Renal impairment
46
Hepatic impairment

(see section 4.3).




St. John’s wort



47
CYP2D6 inhibitors




Alcohol

(see section 4.4).
48

Lithium, tryptophan
Pregnancy
Breast-feeding

49
Fertility

Uncommon Bruxism
Common Diarrhoea,
Constipation,
Vomiting
Elderly patients
aged ≥65 years.
Sexual dysfunction
50
section 5.1) .
Class effect
4.9 Overdose
Mechanism of action

51
increasing dose.

Maintenance
Elderly
as measured by improvement in the MADRS and HAM-D24 total scores.. The effect seen with
analysis).
In the dedicated study in elderly vortioxetine was also effective in these patients.

52
on paediatric use).
Absorption
Vortioxetine is slowly but well absorbed after oral administration and the peak plasma concentration is
reached within 7 to 11 hours. Following multiple dosing of 5, 10, or 20 mg/day, mean Cmax values of
Distribution
Biotransformation
and to a minor extent CYP3A4/5 and CYP2C9 and subsequent glucuronic acid conjugation.
No inhibitory or inducing effect of vortioxetine was observed the drug-drug interaction studies for the
CYP isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or
CYP3A4/5 (see section 4.5). Vortioxetine is a poor P-gp substrate and inhibitor.
53
Elimination
Special populations
Elderly
4.4).
Renal impairment
Hepatic impairment
CYP2D6 gene types

(see section 4.2).
54

6.6).
Tablet core
Mannitol
Magnesium stearate
Tablet coating
Hypromellose
Macrogol 400
Not applicable.
55
6.3 Shelf life
30 months.

Pack sizes of 14, 28, 56, and 98 film-coated tablets.
Perforated unit dose blisters; PVC/PVdC/aluminium.

The pack sizes of 56 x 1 and 98 x 1 film-coated tablets.
Multipack containing: 126 (9 x 14) and 490 (5 x (98 x 1)) film-coated tablets.

requirements.
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
EU/1/13/891/027
EU/1/13/891/028
EU/1/13/891/029
EU/1/13/891/030
EU/1/13/891/031
EU/1/13/891/032
EU/1/13/891/033
EU/1/13/891/034
EU/1/13/891/035
EU/1/13/891/040
56
57
Brintellix 20 mg/ml oral drops, solution
Each ml of solution contains vortioxetine (D,L)-lactate equivalent to 20 mg vortioxetine.
Each drop contains 1 mg vortioxetine.
Excipients with known effect: Each drop contains 4.25 mg of ethanol.
Oral drops, solution.
Clear, nearly colourless to yellowish solution.
Posology
65 years of age.

5 mg corresponding to 5 drops.
58
Special populations
Elderly patients

(see section 4.5).


The oral drops can be taken with or without food.
The drops can be mixed with water, juice or other non-alcoholic drinks.
stages of recovery.
59
Seizures

Mania/hypomania
Haemorrhage
medicinal products known to affect platelet function [e.g. atypical antipsychotics and phenothiazines,
Hyponatraemia
Elderly
60
Renal impairment
Hepatic impairment
Ethanol
This medicinal product contains small amounts of ethanol, less than 100 mg per dose.

(see section 4.3).




61
St. John’s wort

concomitantly using other medicinal products capable of lowering the seizure threshold [e.g.

CYP2D6 inhibitors




Alcohol
62

(see section 4.4).

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

Lithium, tryptophan
Pregnancy
63
Breast-feeding

Fertility
64
Uncommon Bruxism
Common Diarrhoea,
Constipation,
Vomiting
Elderly patients
aged ≥65 years.
Sexual dysfunction
section 5.1) .
Class effect
4.9 Overdose
65
Mechanism of action

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

66
Maintenance
Elderly
In the 8-week double-blind, placebo-controlled, fixed-dose study in elderly depressed patients (aged
analysis).
In the dedicated study in elderly, vortioxetine was also effective in these patients.

67
on paediatric use).
Absorption
Distribution
Biotransformation
and to a minor extent CYP3A4/5 and CYP2C9and subsequent glucuronic acid conjugation.
Elimination
Special populations
Elderly
4.4).
68
Renal impairment
Hepatic impairment
CYP2D6 gene types

metabolisers than in extensive metabolisers. Co-administration of strong CYP3A4/2C9-inhibitors to
(see section 4.2).
(dog), and two incidences of convulsions in dogs in the general toxicity study programme.. A no-effect
69
The active ingredient vortioxetine (D,L)-lactate is currently considered hazardous (persistent,

6.6).
Hydroxypropylbetadex
Ethanol (96 percent)
Purified water
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
2 years
After opening the drops should be used within 8 weeks.
15 ml in an amber glass bottle with dropper applicator (LD-polyethylene), and child-resistant screw
cap (polypropylene).
Pack of 1 glass botlle.
requirements.
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
EU/1/13/891/036
70
71
ANNEX II
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT
72
A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
H. Lundbeck A/S
Ottiliavej 9
DK 2500 Valby
DENMARK
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal products subject to medical prescription.
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING

AUTHORISATION
 Periodic safety update reports
The marketing authorisation holder shall submit the first periodic safety update report for this
product within 6 months following authorisation. Subsequently, the marketing authorisation holder
shall submit periodic safety update reports for this product in accordance with the requirements set
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC and published on the European medicines web-portal.
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND

EFFECTIVE USE OF THE MEDICINAL PRODUCT
 Risk Management Plan (RMP)
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreeed subsequent
updates of the RMP.
An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new
information being received that may lead to a significant change to the benefit/risk profile or as the
result of an important (pharmacovigilance or risk minimisation) milestone being reached.
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same
time.
73
ANNEX III
LABELLING AND PACKAGE LEAFLET
74
A. LABELLING
75
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE
PACKAGING
CARTON AND LABEL

vortioxetine
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each film-coated tablet contains 5 mg vortioxetine (as hydrobromide)
3. LIST OF EXCIPIENTS
4. PHARMACEUTICAL FORM AND CONTENTS
14 film-coated tablets
56x1 film-coated tablets
98x1 film-coated tablets
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Read the package leaflet before use
Oral use
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT

OF THE SIGHT AND REACH OF CHILDREN
Keep out of the sight and reach of children
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP {MM/YYYY}
9. SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
76
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
EU/1/13/891/001 14 film-coated tablets

EU/1/13/891/003 56 x 1 film-coated tablets
EU/1/13/891/004 98 x 1 film-coated tablets
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Brintellix 5 mg
77
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON FOR INTERMEDIATE PACK / COMPONENT OF A MULTIPACK

(WITHOUT BLUE BOX)

vortioxetine
14 Film-coated tablets.
98 x 1 Film-coated tablets.
Component of a multipack, can’t be sold separately.
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
78
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
EU/1/13/891/038 126 film-coated tablets (9 packs of 14)

EU/1/13/891/005 490 film-coated tablets (5 packs of 98x1)
13. BATCH NUMBER
Lot
Brintellix 5 mg
79
OUTER WRAPPER LABEL ON MULTIPACKS WRAPPED IN FOIL

(INCLUDING BLUE BOX)

Vortioxetine
Multipack: 126 (9 packs of 14) film-coated tablets.

Multipack: 490 (5 packs of 98 x 1) film-coated tablets.
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
80
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark

13. BATCH NUMBER
Lot
Brintellix 5 mg
81
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
BLISTER FOR TABLETS

vortioxetine
2. NAME OF THE MARKETING AUTHORISATION HOLDER
H. Lundbeck A/S
3. EXPIRY DATE
EXP (MM/YYYY)
See embossed stamp.
4. BATCH NUMBER
Lot
See embossed stamp.
5. OTHER
82
PACKAGING
CARTON AND LABEL

vortioxetine
56 x 1 film-coated tablets
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
83
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark

EU/1/13/891/009 14 film-coated
EU/1/13/891/013 56x1 film-coated tablets
13. BATCH NUMBER
Lot
Brintellix 10 mg
84

(WITHOUT BLUE BOX)

vortioxetine
14 Film-coated tablets
98 x 1 Film-coated tablets
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
85
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark

13. BATCH NUMBER
Lot
Brintellix 10 mg
86


vortioxetine

Multipacks: 490 (5 packs of 98 x 1) film-coated tablets.
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
87
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark

EU/1/13/891/015 490 film-coated tablets (5 packs of 98x1).
13. BATCH NUMBER
Lot
Brintellix 10 mg
88
BLISTER FOR TABLETS

vortioxetine
H. Lundbeck A/S
3. EXPIRY DATE
EXP (MM/YYYY)
See embossed stamp.
4. BATCH NUMBER
Lot
See embossed stamp.
5. OTHER
89
PACKAGING
CARTON AND LABEL

vortioxetine
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
90
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark

13. BATCH NUMBER
Lot
Brintellix 15 mg
91

(WITHOUT BLUE BOX)

vortioxetine
98 x 1 Film-coated tablets.
Component of a multipack, can’t be sold seperatly.
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
92
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
13. BATCH NUMBER
Lot
Brintellix 15 mg
93


vortioxetine
Multipack: 490 (5 packs of 98x1) film-coated tablets.
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
94
13. BATCH NUMBER
Lot
Brintellix 15 mg
95
BLISTER FOR TABLETS

vortioxetine
H. Lundbeck A/S
3. EXPIRY DATE
EXP (MM/YYYY)
See embossed stamp.
4. BATCH NUMBER
Lot
See embossed stamp.
5. OTHER
96
PACKAGING
CARTON AND LABEL

vortioxetine
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
97
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark

13. BATCH NUMBER
Lot
Brintellix 20 mg
98

(WITHOUT BLUE BOX)

vortioxetine
14 Film-coated tablets
98 x 1 Film-coated tablets
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
99
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark

13. BATCH NUMBER
Lot
Brintellix 20 mg
100


Vortioxetine

Multipack: 490 (5 packs of 98x1) film-coated tablets.
Oral use

8. EXPIRY DATE
EXP {MM/YYYY}

APPROPRIATE
101
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark

13. BATCH NUMBER
Lot
Brintellix 20 mg
102
BLISTER FOR TABLETS

vortioxetine
H. Lundbeck A/S
3. EXPIRY DATE
EXP (MM/YYYY)
See embossed stamp.
4. BATCH NUMBER
Lot
See embossed stamp.
5. OTHER
103
PACKAGING
CARTON AND LABEL FOR BOTTLE

vortioxetine
Each drop contains 1 mg vortioxetine (as (D,L)- lactate)
Contains ethanol
Oral drops, solution

15 ml
Oral use

Keep out of the sight and reach of children.
8. EXPIRY DATE
EXP {MM/YYYY}
When opened, use within 8 weeks

APPROPRIATE
104
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
EU/1/13/891/036 15 ml
13. BATCH NUMBER
Lot
Brintellix 20 mg/ml
105
B. PACKAGE LEAFLET
106
Package leaflet: Information for the patient

Vortioxetine
▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety
information. You can help by reporting any side effects you may get. See the end of section 4 for how
to report side effects.
Read all of this leaflet carefully before you start taking this medicine because it contains
important information for you.
- Keep this leaflet. You may need to read it again.

- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,
even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What Brintellix is and what it is used for

2. What you need to know before you take Brintellix
3. How to take Brintellix
4. Possible side effects
5. How to store Brintellix
6. Contents of the pack and other information
Brintellix contains the active substance vortioxetine. It belongs to a group of medicines called
antidepressants and you have been given this medicine to treat your depression.
Brintellix has been shown to reduce the broad range of depressive symptoms, including sadness, inner
tension (feeling anxious), sleep, disturbances (reduced sleep), reduced appetite, difficulty in
concentrating, feelings of worthlessness, loss of interest in favourite activities, feeling of being slowed
down.
Brintellix is used to treat major depressive episodes in adults.
Do not take Brintellix:
- if you are allergic to vortioxetine or any of the other ingredients of this medicine (listed in
section 6).
- if you are taking other medicines for depression known as non-selective monoamine oxidase
inhibitors or selective MAO-A inhibitors. Ask your doctor if you are uncertain.
Warnings and precautions
Talk to your doctor or pharmacist before taking Brintellix if you:
- are taking medicines with a so-called serotonergic effect, such as:
107
- tramadol (a strong painkiller).
- sumatriptan and similar medicines with active substance names ending in “triptans” (used
to treat migraine).
Taking these medicines together with Brintellix may increase the risk of serotonin syndrome.
This syndrome may be associated with hallucinations, involuntary twitching, accelerated
heartbeat, high blood pressure, fever, nausea and diarrhoea.
- have had fits (seizures).

Your doctor will treat you cautiously if you have a history of fits or have unstable fit
disorders/epilepsy. Fits are a potential risk with medicines used to treat depression. Treatment
should be discontinued in any patient who develops fits or where there is an increase in the
frequency of fits.
- have had mania

- have a tendency to bleed or bruise easily.
- have low sodium level in the blood.
- are 65 years of age or older.
- have a severe kidney disease.
- have a severe liver disease or a liver disease called cirrhosis.
Thoughts of suicide and worsening of your depression
If you are depressed and/or have anxiety disorders you can sometimes have thoughts of harming or
killing yourself. These may be increased when first starting antidepressants, since these medicines all
take time to work, usually about two weeks but sometimes longer.
You may be more likely to think like this if you:

- have previously had thoughts about killing or harming yourself.
- are a young adult.
Information from clinical trials has shown an increased risk of suicidal behaviour in adults aged less
than 25 years with psychiatric conditions who were treated with an antidepressant.
If you have thoughts of harming or killing yourself at any time, contact your doctor or go to a hospital
straight away. You may find it helpful to tell a relative or close friend that you are depressed or have
an anxiety disorder, and ask them to read this leaflet. You might ask them to tell you if they think your
depression or anxiety is getting worse, or if they are worried about changes in your behaviour.
Children and adolescents
Brintellix is not recommended in children and adolescents under 18 years due to lack of information
for this age group.
Other medicines and Brintellix
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other
medicines.
Please tell your doctor if you are taking any of the following medicines:
- phenelzine, iproniazid, isocarboxazid, nialamidetranylcypromine (medicines to treat depression

called non-selective monoamine oxidase inhibitors).
If you have taken any of these medicines, you will need to wait 14 days before you start taking
Brintellix. After stopping this medicine you must allow 14 days before taking any of these
medicines.
108
- moclobemide (a medicine to treat depression).
- selegiline, rasagiline (medicines to treat Parkinson’s disease).
- linezolid (a medicine to treat bacterial infections).
- lithium (a medicine to treat depression and mental disorders) or tryptophan.
- medicines know to cause low sodium level.
- rifampicin (a medicine to treat tuberculosis and other infections).
- carbamazepine, phenytoin (medicines to treat epilepsy or other illness).
- warfarin, dipyridamole, phenprocoumon, low-dose acetylsalicylic acid (blood thinning
medicines).
Medicines that increase the risk of fits:

- sumatriptan and similar medicines with active substance names ending in “triptans”.
- mefloquine (a medicine to prevent and treat malaria).
- bupropion (a medicine to treat depression also used to wean from smoking).
- fluoxetine, paroxetine and other medicines to treat depression called SSRI/SNRIs, tricyclics.
- St John’s wort (hypericum perforatum) (a medicine to treat depression).
- quinidine (a medicine to treat heart rhythm disorders).
- chlorpromazine, chlorprothixene, haloperidol (medicines to treat mental disorders belonging to
the groups called phenothiazines, thioxanthenes, butyrophenones).
Please tell your doctor if you are taking any of the medicines above, since your doctor needs to know
if you already are at risk for siezures.
Brintellix with alcohol
As with many medicines, combining this medicine with alcohol is not advisable.
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor for advice before taking this medicine.
Pregnancy
Brintellix should not be used during pregnancy unless the doctor says it is absolutely necessary.
If you take medicines to treat depression, including Brintellix, during the last 3 months of your
pregnancy, you should be aware that the following effects may be seen in your newborn baby: trouble
with breathing, bluish skin, fits, body temperature changes, feeding difficulties, vomiting, low blood
sugar, stiff or floppy muscles, vivid reflexes, tremor, jitteriness, irritability, lethargy, constant crying,
sleepiness and sleeping difficulties. Contact your doctor immediately if your newborn baby has any of
these symptoms.
Make sure your midwife and/or doctor know you are on Brintellix. When taken during pregnancy,
particularly in the last 3 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. If this happens to your baby, you should contact your midwife and/or doctor
immediately.
Breast-feeding
It is expected that the ingredients of Brintellix will pass into breast milk. Brintellix is not to be used
during breast-feeding. Your doctor will make a decision on whether you should stop breast-feeding, or
stop using Brintellix taking into account the benefit of breast-feeding for your child, and the benefit of
therapy for you.
109
Fertility
Some antidepressant medicines like vortioxetine may reduce the quality of sperm in animals.
Theoretically, this could affect fertility. Vortioxetine has not shown this effect in animal studies;
impact on humans has not been observed as yet.
Driving and using machines
Brintellix has no or negligible influence on the ability to drive and use machines. However, caution is
advised during such activities when beginning Brintellix treatment or changing the dose.
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist
if you are not sure.
The recommended dose of Brintellix is 10 mg vortioxetine taken as one daily dose in adults less than
65 years of age. The dose may be increased by your doctor to a maximum of 20 mg vortioxetine per
day or lowered to a minimun of 5 mg vortioxetine per day depending on your response to treatment.
For elderly people 65 years af age or older, the starting dose is 5 mg vortioxetine taken once daily.
Take one tablet with a glass of water.

The tablet can be taken with or without food.
Duration of treatment
Take Brintellix for as long as your doctor recommends.
Continue to take Brintellix even if it takes some time before you feel any improvement in your
condition.
Treatment should be continued for at least 6 months after you feel well again.
If you take more Brintellix than you should
If you take more than the prescribed dose of Brintellix, contact your doctor or nearest hospital
emergency department immediately. Have the container and any remaining tablets available. Do this
even if there are no signs of discomfort. Overdose signs are dizziness, nausea, diarrhoea, stomach
discomfort, itching of the whole body, sleepiness and flushing.
If you forget to take Brintellix
Take the next dose at the usual time. Do not take a double dose to make up for a forgotten dose.
If you stop taking Brintellix
Do not stop taking Brintellix without talking with your doctor.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
110
Like all medicines, this medicine can cause side effects, although not everybody gets them.
In general, the observed side effects were mild to moderate and occurred within the first two weeks of
treatment. The reactions were usually temporary and did not lead to cessation of therapy.
Side effects listed below have been reported in the following frequencies.
Very common: may affect more than 1 in 10 people

- nausea
Common: may affect up to 1 in 10 people

- diarrhoea, constipation, vomiting
- dizziness
- itching of the whole body
- decreased appetite
- abnormal dreams
Uncommon: may affect up to 1 in 100 people

- grinding one’s teeth
- flushing
- night sweats
Not known: frequency cannot be estimated from available data

- serotonin syndrome (see section 2)
An increased risk of bone fractures has been observed in patients taking this type of medicines.
Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V*. By reporting side effects, you can help provide more information on the safety
of this medicine.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date that is stated on the packaging after EXP. The expiry
date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to
throw away medicines you no longer use. These measures will help to protect the environment.
What Brintellix contains
- The active substance is vortioxetine. Each film-coated tablet contains 5 mg vortioxetine (as
hydrobromide).
111
- The other ingredients are mannitol (E421), microcrystalline cellulose, hydroxypropylcellulose,
sodium starch glycolate (type A), magnesium stearate, hypromellose, Macrogol 400, titanium
dioxide (E171), iron oxide red (E172).
What Brintellix looks like and contents of the pack
Pink, almond-shaped 5 x 8.4 mm film-coated tablet marked with “TL” on one side and “5” on the
other side.
Brintellix film-coated tablets 5 mg are available in blister packs of 14, 28, 98, 56x1, 98x1,
126 (9x14) 490 (5x(98x1)) tablets and in tablet containers of 100 and 200 tablets.
The pack sizes of 56 x 1, 98 x 1 and 490 film-coated tablets are presented in unit dose blister.
Marketing Authorisation Holder and Manufacturer
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
Belgique/België/Belgien Lietuva
Lundbeck S.A./N.V. UAB Lundbeck Lietuva
Tél/Tel: +32 2 340 2828 Tel: + 370 5 231 4188
България Luxembourg/Luxemburg
Lundbeck Export A/S Representative Office Lundbeck S.A.
Tel: +359 2 962 4696 Tél: +32 2 340 2828
Česká republika Magyarország

Lundbeck Česká republika s.r.o. Lundbeck Hungaria Kft.
Tel: +420 225 275 600 Tel: +36 1 4369980
Danmark Malta
Lundbeck Pharma A/S H. Lundbeck A/S
Tlf: +45 4371 4270 Tel: + 45 36301311
Deutschland Nederland
Lundbeck GmbH Lundbeck B.V.
Tel: +49 40 23649 0 Tel: +31 20 697 1901
Eesti Norge
Lundbeck Eesti AS H. Lundbeck AS
Tel: + 372 605 9350 Tlf: +47 91 300 800
Ελλάδα Österreich
Lundbeck Hellas S.A. Lundbeck Austria GmbH
Τηλ: +30 210 610 5036 Tel: +43 1 331 070
112
España Polska
Lundbeck España S.A. Lundbeck Poland Sp. z o. o.
Tel: +34 93 494 9620 Tel.: + 48 22 626 93 00
France Portugal
Lundbeck SAS Lundbeck Portugal Lda
Tél: + 33 1 79 41 29 00 Tel: +351 21 00 45 900
Hrvatska România
Lundbeck Croatia d.o.o. Lundbeck Export A/S
Tel.: + 385 1 3649 210 Tel: +40 21319 88 26
Ireland Slovenija
Lundbeck (Ireland) Limited Lundbeck Pharma d.o.o.
Tel: +353 1 468 9800 Tel.: +386 2 229 4500
Ísland Slovenská republika

Lundbeck Export A/S, útibú á Íslandi Lundbeck Slovensko s.r.o.
Tel: +354 414 7070 Tel: +421 2 5341 42 18
Italia Suomi/Finland
Lundbeck Italia S.p.A. Oy H. Lundbeck Ab
Tel: +39 02 677 4171 Puh/Tel: +358 2 276 5000
Κύπρος Sverige
Lundbeck Hellas A.E H. Lundbeck AB
Τηλ.: +357 22490305 Tel: +46 4225 4300
Latvija United Kingdom

SIA Lundbeck Latvia Lundbeck Limited
Tel: + 371 6 7 067 884 Tel: +44 1908 64 9966
This leaflet was last revised in MM/YYYY
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu.
113

Vortioxetine


down.
section 6).
- if you are taking other medicines known for depression as non-selective monoamine oxidase
114
- tramadol (a strong pain killer))
to treat migraine).

disorder/epilepsy. Fits are a potential risk with medicines used to treat depression. Treatment
frequency of fits.
- have had mania


for this age group.
medicines.
- phenelzine, iproniazid, isocarboxazid, nialamide, tranylcypromine (medicines to treat

depression called non-selective monoamine oxidase inhibitors).
Brintellix. After stopping this medicine, you must allow 14 days before taking any of these
medicines.

115
- medicines known to cause low sodium level.
- rifampicin (a medicine to treat tuberculosis and other infections)
- cabamazepine, phenytoin (medicines to treat epilepsy or other illness)
- Warfarin, dipyridamole, phenprocoumon, low-dose acetylsalicylic acid (blood thinning
medicines).

- fluoxetine, paraoxetine and other medicines to treat depression called SSRI/SNRIs, tricyclics
- St John’s wort (hypericum perforatum)(a medicine to treat depression).
the group called phenothiazines, thioxanthenes, butyrophenones).
Please tell your doctor if you are taking any of the medicines above, since your doctor needs to know
if you already are at risk for seizure.
Pregnancy
Brintellix should not be used during pregnancy unless thedoctor says it is absolutely necessary.
If you take medicine to treat depression, including Brintellix, during the last 3 months of your
these symptoms.
immediately.
Breast-feeding
therapy for you
116
Fertility
For elderly people 65 years af age or older the starting dose is 5 mg vortioxetine taken once daily.

condition.
even if there are no signs of discomfort. Overdose signs could be dizziness, nausea, diarrhoea,
stomach discomfort, itching of the whole body, sleepiness and flushing.
117

- nausea

- dizziness
- abnormal dreams
Uncommon: may affect up to 1 in 100

- flushing
- night sweats

An increased risk of bone freactures has been observed in patients taking this type of medicines.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects
not listed in this leaflet. You can also report side effects directly via the national reporting system
listed in Appendix V*. By reporting side effects, you can help provide more information on the safety
of this medicine.
hydrobromide).
118
dioxide (E171), iron oxide yellow (E172).
Yellow, almond-shaped 5 x 8.4 mm film-coated tablets marked with “TL” on one side and “10” on the
other side.
Brintellix film-coated tablets 10 mg are available in blister packs of 7, 14, 28, 56, 56 x 1, 98, 98 x 1,
126 (9x14), 490 (5 x (98x1)) tablets and in tablet containers of 100 and 200 tablets.
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
Tél/Tel: +32 2 340 2828 Tel: + 370 5 231 4188
Tel: +359 2 962 4696 Tél: +32 2 340 2828

Tel: +420 225 275 600 Tel: +36 1 4369980
Danmark Malta
Tlf: +45 4371 4270 Tel: + 45 36301311
Tel: +49 40 23649 0 Tel: +31 20 697 1901
Eesti Norge
Tel: + 372 605 9350 Tlf: +47 91 300 800
Τηλ: +30 210 610 5036 Tel: +43 1 331 070
119
España Polska
Tel: +34 93 494 9620 Tel.: + 48 22 626 93 00
France Portugal
Tél: + 33 1 79 41 29 00 Tel: +351 21 00 45 900
Hrvatska România
Tel.: + 385 1 3649 210 Tel: +40 21319 88 26
Ireland Slovenija
Tel: +353 1 468 9800 Tel.: +386 2 229 4500

Tel: +354 414 7070 Tel: +421 2 5341 42 18
Tel: +39 02 677 4171 Puh/Tel: +358 2 276 5000
Τηλ.: +357 22490305 Tel: +46 4225 4300

Tel: + 371 6 7 067 884 Tel: +44 1908 64 9966
http://www.ema.europa.eu
120

Vortioxetine


Brintellix contains the active substance vortioxetine.It belongs to a group of medicines called
down.
section 6).
121
- sumatriptan and similar medicines to Brintellix with active substance names ending in
“triptans” (used to treatmigraine).

disorders/elpilepsy. Fits are a potential risk with medicines used to treat depression. Treatment
frequency of fits.
- have had mania.

- have a tendency bleed or bruise easily.
- have a severe kidney disease..

for this age group.
medicines.
depression called non-selectve monoamine oxidase inhibitors).
medicines.
122
- linezolid (a medicine to treat bacterial infections) .
- cabamazepine, phenytoin (medicines to treat epilepsy or other illness).
medicines).

- fluoxetine, paroxetine and other medicine to treat depression called SSRI/SNRIs, tricyclics.
Please tell your doctor if you are taking any of the medicine above, since your doctor needs to know if
you already are at risk for seizures.
Pregnancy
these symptoms.
immediately.
Breast-feeding
therapy for you
123
Fertility
For elderly people 65 years af age or older the starting dose is 5 mg vortioxetine taken once daily.

condition.
124

- nausea

- dizziness
- abnormal dreams
Uncommon to rare: may affect up to 1 in 100

- flushing
- night sweats

An increased risk of bone fracture has been observed in patients taking this type of medicines.

If you get any side effects, talk to your doctor or pharmacis. This includes any possible side effects not
listed in this leaflet. You can also report side effects directly via the national reporting system listed in
Appendix V*. By reporting side effects, you can help provide more information on the safety of this
medicine.
hydrobromide).
125
dioxide (E171), iron oxide yellow (E172), iron oxide red (E172)
Orange, almond-shaped 5 x 8.4 mm film-coated tablet marked with “TL” on one side and “15” on the
other side.
Brintellix film-coated tablets 15 mg are available in blister packs of 14, 28, 56, 56 x 1, 98, 98 x 1, 490
(5 x (98x1)) tablets and in tablet containers of 100 and 200 tablets.
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
Tél/Tel: +32 2 340 2828 Tel: + 370 5 231 4188
Tel: +359 2 962 4696 Tél: +32 2 340 2828

Tel: +420 225 275 600 Tel: +36 1 4369980
Danmark Malta
Tlf: +45 4371 4270 Tel: + 45 36301311
Tel: +49 40 23649 0 Tel: +31 20 697 1901
Eesti Norge
Tel: + 372 605 9350 Tlf: +47 91 300 800
Τηλ: +30 210 610 5036 Tel: +43 1 331 070
126
España Polska
Tel: +34 93 494 9620 Tel.: + 48 22 626 93 00
France Portugal
Tél: + 33 1 79 41 29 00 Tel: +351 21 00 45 900
Hrvatska România
Tel.: + 385 1 3649 210 Tel: +40 21319 88 26
Ireland Slovenija
Tel: +353 1 468 9800 Tel.: +386 2 229 4500

Tel: +354 414 7070 Tel: +421 2 5341 42 18
Tel: +39 02 677 4171 Puh/Tel: +358 2 276 5000
Τηλ.: +357 22490305 Tel: +46 4225 4300

Tel: + 371 6 7 067 884 Tel: +44 1908 64 9966
127

Vortioxetine


down.
section 6).
128
- taking medicines with a so-called serotonergic effect, such as:
- tramadol (a strong pain killer).
- sumatriptan and similar medicines ending in “triptans” (used to treat migraine).

disorders/epilepsy. Fits are a potential risk with medicines used to treat depressionTreatment
frequency of fits.
- have had mania

- have a tendency bleed or bruise easily.

for this age group.
medicines.
medicines.
129
- selegiline and rasagiline (medicines to treat Parkinson’s disease).
- lithium (a medicine to treat depression and mental disorders) or tryptophan-
medicines).

- sumatriptan and similar medicines with active substance names ending in “triptans”
- mefloquine (a medicine to prevent and treatmalaria).
- chlorpromaine, chlorprothixene, haloperidol (medicines to treat mental disorders belonging to
the group called phenothiazines, thioxanthenes,butyrophenones).
you already are at risk for seizures.
Pregnancy
If you take medicine to treat depression including Brintellix during the last 3 months of your
pregnancy you should be aware that the following effects may be seen in your newborn baby: trouble
these symptoms.
after the baby is born. If this happens to your baby you should contact your midwife and/or doctor
immediately.
Breast-feeding¨
therapy for you
130
Fertility
The normally recommended dose of Brintellix is 10 mg vortioxetine taken as one daily dose in adults
less than 65 years of age. The dose may be increased by your doctor to a maximum of 20 mg
vortioxetine per day or lowered to a minimun of 5 mg vortioxetine per day depending on your
response to treatment.
For elderly 65 years af age or older the starting dose is 5 mg vortioxetine taken once daily.

condition.
even if there are no signs of discomfort. Overdose signs could be dizziness, nausea, diarrhoea,
stomach discomfort, itching of the whole body, sleepiness and flushing.
131

- nausea

- dizziness
- abnormal dreams
Uncommon: may affect up to 1 in 100

- flushing
- night sweats

An increased risk of bone fracture has beenobserved in patients taking this type of medicines.

medicine.
hydrobromide).
132
dioxide (E171), iron oxide red (E172).
Red, almond-shaped 5 x 8.4 mm film-coated tablet marked with “TL” on one side and “20” on the
other side.
Brintellix film-coated tablets 20 mg are available in blister packs of 14, 28, 56, 56x1, 98, 98x1, 126
(9x14), 490 (5x(98x1)) tablets and in tablet containers of 100, 200 tablets.
The pack sizes of 56 x1, 98 x1 and 490 film-coated tablets are presented in unit dose blister.
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
Tél/Tel: +32 2 340 2828 Tel: + 370 5 231 4188
Tel: +359 2 962 4696 Tél: +32 2 340 2828

Tel: +420 225 275 600 Tel: +36 1 4369980
Danmark Malta
Tlf: +45 4371 4270 Tel: + 45 36301311
Tel: +49 40 23649 0 Tel: +31 20 697 1901
Eesti Norge
Tel: + 372 605 9350 Tlf: +47 91 300 800
Τηλ: +30 210 610 5036 Tel: +43 1 331 070
133
España Polska
Tel: +34 93 494 9620 Tel.: + 48 22 626 93 00
France Portugal
Tél: + 33 1 79 41 29 00 Tel: +351 21 00 45 900
Hrvatska România
Tel.: + 385 1 3649 210 Tel: +40 21319 88 26
Ireland Slovenija
Tel: +353 1 468 9800 Tel.: +386 2 229 4500

Tel: +354 414 7070 Tel: +421 2 5341 42 18
Tel: +39 02 677 4171 Puh/Tel: +358 2 276 5000
Τηλ.: +357 22490305 Tel: +46 4225 4300

Tel: + 371 6 7 067 884 Tel: +44 1908 64 9966
134

Vortioxetine


Brintellix contains the active substance vortioxetine.It belongs to a group of medicines called
down.
section 6).
135
- tramadol (a strong pain killer).
to treat migraine).

disorders/epilepsy. Fits are a potential risk with medicines used to treat depression.Treatment
frequency of fits.
- have had mania.


for this age group.
medicines.
medicines.
136
- selegiline and rasagiline (medicines to treat Parkinson’s disease).
- lithium (a medicine to treat depression an d mental disorders) or tryptophan.
medicines).

- St John’s wort (hypericum perforatum)(a medicine to treat depression).
- Chlorpromazine, chlorprothixene, haloperidol (medicines to treat mental disorders and belong to
you already are at risk for seizure.
Pregnancy
these symptoms.
immediately.
Breast-feeding
137
therapy for you
Fertility
Brintellix contains ethanol. This medicine contains small amounts of ethanol (alcohol), less than
100 mg per dose.
The recommended dose of Brintellix is 10 mg vortioxetine taken as one daily dosein adults less than
For elderly 65 years af age or older the starting dose is 5 mg vortioxetine taken once daily.
Brintellix can be taken with or without food.

The drops can be mixed with water, juice or other non-alcoholic drinks.
Brintellix oral drops are not to be mixed with other medicinal products.
condition.
emergency department immediately. Have the bottle and any remaining solution available. Do this
138

- nausea

- dizziness
- abnormal dreams
Uncommon may affect up to1in 100

- flushing
- night sweats

An increased risk of bone fractures has been observed in patients taking this type of medicines.

medicine.
139
After first opening the drops should be used within 8 weeks.
- The active substance is vortioxetine. Each drop of solution contains 1 mg vortioxetine (as (D,L)-
lactate).
- The other ingredients are hydroxypropylbetadex, ethanol (96 percent) and purified water

Oral drops, solution
Clear, nearly colourless to yellowish solution.
Brintellix oral drops, solution, are available in 20 ml amber glass bottles.

Each bottle contains 15 ml Brintellix oral drops, solution.
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
Tél/Tel: +32 2 340 2828 Tel: + 370 5 231 4188
Tel: +359 2 962 4696 Tél: +32 2 340 2828

Tel: +420 225 275 600 Tel: +36 1 4369980
Danmark Malta
Tlf: +45 4371 4270 Tel: + 45 36301311
Tel: +49 40 23649 0 Tel: +31 20 697 1901
Eesti Norge
Tel: + 372 605 9350 Tlf: +47 91 300 800
140
Τηλ: +30 210 610 5036 Tel: +43 1 331 070
España Polska
Tel: +34 93 494 9620 Tel.: + 48 22 626 93 00
France Portugal
Tél: + 33 1 79 41 29 00 Tel: +351 21 00 45 900
Hrvatska România
Tel.: + 385 1 3649 210 Tel: +40 21319 88 26
Ireland Slovenija
Tel: +353 1 468 9800 Tel.: +386 2 229 4500

Tel: +354 414 7070 Tel: +421 2 5341 42 18
Tel: +39 02 677 4171 Puh/Tel: +358 2 276 5000
Τηλ.: +357 22490305 Tel: +46 4225 4300

Tel: + 371 6 7 067 884 Tel: +44 1908 64 9966
141
Annex IV
Scientific conclusions and grounds recommending the variation to the terms of the Marketing
Authorisation
142
Scientific conclusions
Taking into account the PRAC Assessment Report on the PSUR for Brintellix, the scientific
conclusions of PRAC are as follows:
During the reporting period, 9 cases of serotonin syndrome were received.
An analysis of these cases led to the conclusion that in a number of cases a causal role of
vortioxetine could not be excluded (plausible temporal relationship, recovery upon discontinuation
of vortioxetine).
Moreover, in a number of reported cases, the diagnosis of serotonin syndrome has been established
by a physician and the event has been considered as possibly related by the reporter.
Furthermore, based on a “class effect”, serotonin syndrome is currently considered as a potential
risk in the RMP and based on this Serotonin Syndrome is mentioned in section 4.4 of the SmPC.
Considering, the possibly related cases, the pharmacologic properties of vortioxetine and the SmPC
guideline that states that any adverse reactions described in section 4.4 or known to result from
conditions mentioned here should also be included in section 4.8, it the PRAC concluded that
Serotonin Syndrome should be listed in section 4.8 of the SmPC with an unknown frequency.
Therefore, in view of available data regarding serotonin syndrome, the PRAC considered that
changes to the product information were warranted.
The CHMP agrees with the scientific conclusions made by the PRAC.
Grounds recommending the variation to the terms of the Marketing Authorisation
On the basis of the scientific conclusions for Brintellix, the CHMP is of the opinion that the benefit-
risk balance of the medicinal product containing the active substance vortioxetine is favourable
subject to the proposed changes to the product information.
The CHMP recommends that the terms of the Marketing Authorisation(s) should be varied.
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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Brintellix 5 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

4.1 Therapeutic indications

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

4.2 Posology and method of administration

Depending on individual patient response, the dose may be increased to a maximum of 20 mg

Cytochrome P450 inducers

Brintellix is for oral use.

4.4 Special warnings and precautions for use

Use in paediatric population

Suicide/suicidal thoughts or clinical worsening

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

Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS), potentially life-threatening

Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by

Potential for other medicinal products to affect vortioxetine

Irreversible non-selective MAOIs

Reversible, selective MAO-A inhibitor (moclobemide)

Reversible, non-selective MAOI (linezolid)

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

Serotonergic medicinal products

St. John’s wort

Medicinal products lowering the seizure threshold

ECT (electroconvulsive therapy)

CYP3A4 inhibitors and CYP2C9 inhibitors

Interactions in CYP2D6 poor metabolisers

No inhibitory effect of 40 mg single-dose omeprazole (CYP2C19 inhibitor) was observed on the

Cytochrome P450 inducers

Potential for vortioxetine to affect other medicinal products

Anticoagulants and antiplatelet medicinal products

No pharmacodynamic interactions were observed. No significant impairment, relative to placebo, in

4.6 Fertility, pregnancy and lactation

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

A risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

4.7 Effects on ability to drive and use machines

4.8 Undesirable effects

Summary of the safety profile

Tabulated list of adverse reactions

SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION

Description of selected adverse reactions

Reporting of suspected adverse reactions

There is limited experience with vortioxetine overdose.

5.1 Pharmacodynamic properties

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

The mechanism of action of vortioxetine is thought to be related to its direct modulation of

Clinical efficacy and safety

The efficacy of vortioxetine 10 or 20 mg/day was further demonstrated in a 12-week, double-blind,

Tolerability and safety

5.2 Pharmacokinetic properties

The major metabolite of vortioxetine is pharmacologically inactive.

CYP2D6 gene types

In CYP2D6 ultra-rapid metabolisers, the plasma concentration of vortioxetine 10 mg/day were