Brintellix Tablets

BRINTELLIX is indicated for the treatment of major depressive disorder and to reduce the risk of relapse.

Posology
BRINTELLIX is for oral use in adults. The starting and recommended dose of BRINTELLIX is 10 mg once daily. 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. If a dose increase is required, this should be in periods of not less than one week of the treatment. A dose decrease may be considered for patients who do not tolerate higher doses. BRINTELLIX can be taken without regard to meals. After the depressive symptoms resolve, treatment for at least 6 months is recommended for consolidation of the antidepressive response. Patients being treated with BRINTELLIX can abruptly stop taking BRINTELLIX without the need for a gradual reduction in dose.
Special populations
Elderly patients
The safety and efficacy of BRINTELLIX have been established in elderly patients. However, caution should be exercised when treating the elderly. Treatment should be initiated with 5 mg daily and, depending on the individual patient response, the dose may be increased to 10 mg daily. Limited data are available with doses exceeding 10 mg daily.
Paediatric patients
The safety and efficacy of BRINTELLIX in children aged years and adolescents aged less than 18 years have not been established. No data are available.
Renal or hepatic impairment
No dose adjustment is needed based on renal or hepatic function (see Section 4.4 and 5.2).
Cytochrome P450 inhibitors
Depending on individual patient response, a lower dose of BRINTELLIX may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to BRINTELLIX treatment (see Section 4.5).
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, carbamazepine, phenytoin) is added to BRINTELLIX treatment (see Section 4.5).
Method of administration
BRINTELLIX is for oral use. The film-coated tablets can be taken with or without food.

Hypersensitivity to vortioxetine or to any of the excipients of BRINTELLIX. Concomitant use of BRINTELLIX with monoamine oxidase inhibitors (MAOIs) (see Section 4.5).

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 BRINTELLIX 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, and 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 with BRINTELLIX, 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 with BRINTELLIX. A meta-analysis of placebo-controlled clinical trials 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 with BRINTELLIX especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.
Seizures
Seizures are a potential risk with antidepressants, including BRINTELLIX. Therefore, BRINTELLIX should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy. Treatment with BRINTELLIX should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency.
Serotonin syndrome or neuroleptic malignant syndrome
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 medicines (including opioids and triptans), with medicines which impair 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 Section 4.3 and Section 4.5). Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g. hyperreflexia, incoordination) 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.
Hyponatraemia
Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported with the use of antidepressants with serotonergic effect (SSRIs/SNRIs). Caution should be exercised in patients at risk, such as the elderly, cirrhotic patients or patients concomitantly treated with medications known to cause hyponatraemia. Discontinuation of BRINTELLIX should be considered in patients with symptomatic hyponatraemia and appropriate medical intervention should be instituted.
Glaucoma
Mydriasis has been reported in association with use of antidepressants, including BRINTELLIX. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma. Caution is advised when prescribing BRINTELLIX to patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.
Activation of hypomania or mania
BRINTELLIX treatment should be used with caution in patients with a history of mania/hypomania, and should be discontinued in any patient entering a manic phase.
Aggression/agitation
Patients treated with antidepressants, including BRINTELLIX, may also experience feelings of aggression, anger, agitation and irritability. Patientu2019s condition and disease status should be closely monitored. Patients (and caregivers of patients) should be alerted to seek medical advice, if aggressive/agitated behaviour emerges or aggravates.
Haemorrhage
Bleeding abnormalities, such as ecchymoses, purpura and other haemorrhagic events such as gastrointestinal or gynaecological bleeding may occur with BRINTELLIX. SSRIs/SNRIs may increase the risk of postpartum haemorrhage, and this risk could potentially apply also to BRINTELLIX (see section 4.6). Caution is advised in patients taking anticoagulants and/or medicinal products known to affect platelet function, e.g., atypical antipsychotics and phenothiazines, most tricyclic antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs), or aspirin (see Section 4.5), and in patients with known bleeding tendencies/disorders.
Co-administration with cytochrome P450 inhibitors
Co-administration of BRINTELLIX and bupropion resulted in a higher incidence of adverse reactions 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, quinidine, fluoxetine, paroxetine) are added to BRINTELLIX treatment (see Section 4.2 and Section 4.5).
Renal or hepatic impairment
Given that subjects with renal or hepatic impairment are vulnerable and given that the data on the use of BRINTELLIX in these subpopulations are limited, caution should be exercised when treating these patients (see Section 4.2 and 5.2).
Brintellix contains Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially u2018sodium - freeu2019.
Brintellix contains Mannitol
BRINTELLIX contains sugar (mannitol) which may have an effect on the glycaemic control of patients with diabetes mellitus.

Vortioxetine is extensively metabolised in the liver primarily through oxidation and subsequent glucuronic acid conjugation. In vitro, the cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 are involved in the metabolism of vortioxetine (see Section 5.2).
Monoamine Oxidase Inhibitors (MAOIs)
Due to the risk of serotonin syndrome, BRINTELLIX is contraindicated in any combination with MAOIs. BRINTELLIX must not be initiated for at least 14 days after discontinuation of treatment with an MAOI. BRINTELLIX must be discontinued for at least 14 days before starting treatment with an MAOI (see Section 4.3).
Linezolid
The antibiotic linezolid is a weak MAOI and should not be given to patients treated with BRINTELLIX. Close monitoring for serotonin syndrome is necessary if used concomitantly (see Section 4.4).
Serotonergic medicines
Co-administration of antidepressants with medicines with a serotonergic effect e.g., opioids (including pethidine, tramadol) and triptans (including sumatriptan) may lead to serotonin syndrome (see Section 4.4).
St. Johnu2019s Wort
Concomitant use of antidepressants with serotonergic effect, and herbal remedies containing. St Johnu00b4s Wort (Hypericum perforatum) may result in a higher incidence of adverse reactions including serotonin syndrome (see Section 4.4).
Medicines lowering the seizure threshold
Antidepressants with serotonergic effect including BRINTELLIX can lower the seizure threshold. Caution is advised when concomitantly using BRINTELLIX and other medicinal products capable of lowering the seizure threshold (e.g. antidepressants (tricyclics, SSRIs, SNRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquin, bupropion and tramadol) (see Section 4.4).
ECT (electroconvulsive therapy)
There is no clinical experience with 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 twice daily for 14 days in 44 healthy subjects. The co-administration resulted in a higher incidence of adverse reactions 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, quinidine, fluoxetine, paroxetine) are added to BRINTELLIX treatment (see Section 4.2). When BRINTELLIX 10 mg/day 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 10 mg/day 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. No inhibitory effect of 40 mg single dose omeprazole (CYP2C19 inhibitor) was observed on the multiple dose pharmacokinetics of BRINTELLIX (10 mg/day) in 15 healthy subjects.
Cytochrome P450 inducers
When a single dose of BRINTELLIX 20 mg 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 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 BRINTELLIX treatment (see Section 4.2).
Aspirin
No effect of multiple doses of aspirin 150 mg/day on multiple dose pharmacokinetics of BRINTELLIX 10mg/day was observed in 28 healthy subjects.
Anticoagulants and antiplatelet medicines
No significant effects, relative to placebo, were observed in INR, prothrombin or plasma R-/S- warfarin values following co-administration of BRINTELLIX 10 mg/day 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, caution should be exercised when BRINTELLIX 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).
Alcohol
No significant additional 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. However, the combination with alcohol is not advisable.
Diazepam
No significant impairment, relative to placebo, in cognitive function using a battery of neuropsychological tests was observed for BRINTELLIX 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 (ethinyl estradiol 30 u03bcg/levonorgestrel 150 u03bcg) 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 (see Section 5.2). No inhibitory effect of BRINTELLIX (10 mg/day for 14 days) was observed in healthy subjects for the cytochrome P450 isozymes CYP2C19 (omeprazole, diazepam), CYP2C9 (warfarin), CYP3A4/5 (ethinyl estradiol), or CYP2B6 (bupropion). In a medicine interaction study in healthy subjects, no inhibitory effect of BRINTELLIX 10 mg/day for 14 days was observed for CYP2C9(tolbutamide), CYP1A2 (caffeine), CYP3A4/5 (midazolam), or CYP2D6 (dextromethorphan).
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 such as BRINTELLIX have been given together with lithium or tryptophan, therefore concomitant use of BRINTELLIX with these medicinal products should be undertaken with caution.
Interference with urine drug screens
There have been reports of false positive results in urine enzyme immunoassays for methadone in patients who have taken BRINTELLIX. 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.

Pregnancy
BRINTELLIX should not be taken during pregnancy or by women with child-bearing potential not using contraception. Safety and efficacy in pregnant women has not been established. The following symptoms may occur in the newborn after maternal use of BRINTELLIX 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 have suggested 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 to BRINTELLIX 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).
Breastfeeding
Mothers should not breastfeed their infants when taking BRINTELLIX. The safety of BRINTELLIX in breastfeeding women has not been established. Vortioxetine and/or its metabolites are excreted into the milk of lactating rats.

As adverse reactions such as dizziness have been reported, patients should exercise caution when driving or operating hazardous machinery, especially when starting treatment with BRINTELLIX or when changing the dose.

The most common adverse reaction was nausea. 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 BRINTELLIX was greater than the incidence in placebo-treated patients.
Table 1 Incidence of common adverse events for major depressive disorder, pool of 12 short-term studies
Body System / Adverse Event Percentage of Patients Reporting
BRINTELLIX 5 mg/day (n=1157) BRINTELLIX 10 mg/day (n=1042) BRINTELLIX 15 mg/day (n=449) BRINTELLIX 20 mg/day (n=812) Placebo (n=1968)
Gastrointestinal Disorders Nausea 20,5* 22,6* 31,2* 27,2* 8,1
Diarrhoea 6,6 5,4 9,4* 5,5 5,5
Dry mouth 6,4 5,5 6,0 6,5 5,6
Constipation 3,4 3,6 5,6* 4,4* 2,9
Vomiting 2,7* 3,6* 6,5* 4,4* 1,1
Dyspepsia 1,8 1,7 2,4 2,1 1,9
Flatulence 1,0 1,9 2,0 0,9 1,2
Abdominal discomfort 1,4 0,6 2,0 1,6 1,1
General Disorders and Administration Site Conditions Fatigue 3,1 2,8 3,6 2,6 2,7
Infections and Infestations Naso-pharyngitis 5,3 4,0 3,6 4,9 3,9
Influenza 1,5 1,6 0,9 0,4 1,1
Injury, poisoning and procedural complications Accidental overdose 1,3 1,2 1,3 0,9 1,0
Metabolism and Nutrition Disorders Decreased appetite 2,1* 0,7 0,7 1,6 1,0
Musculoskeletal and Connective Tissue Disorders Back Pain 2,2 2,1 1,8 1,1 1,8
Arthralgia 0,9 0,9 1,8 1,1 0,9
Nervous System Headache 13,7 12,7 14,7 12,4 12,9
Dizziness 5,5 5,2 7,1 6,3 5,3
Somnolence 3,3 2,9 2,7 3,3 2,3
Sedation 1,2 0,5 1,3 1,5* 0,6
Psychiatric Disorders Insomnia 3,1 2,6 1,8 2,7 2,5
Skin and Subcutaneous Tissue Disorders Hyper-hidrosis 2,3 2,3 1,8 0,7 1,7
Pruritus generalised 0,4 1,3* 1,6* 1,8* 0,4
* Adverse events for which the difference to placebo is statistically significant (p<0.05) Adverse reactions are listed below in Table 2 using the following convention: very common (u2265 1/10); common (u2265 1/100 to < 1/10); uncommon (u2265 1/1 000 to < 1/100); rare (u2265 1/10 000 to < 1/1000); very rare (< 1/10 000), not known (cannot be estimated from the available data). The table includes all relevant side effects which occurred more frequently with BRINTELLIX treatment than with placebo treatment in clinical trials and post-marketing experience.
Table 2 Frequencies of adverse reactions
SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION
Immune system disorders Not known* Anaphylactic reaction
Endocrine disorders Not known* Hyperprolactinaemia
Metabolism and nutrition disorders Not known* Hyponatraemia
Psychiatric disorders Common Abnormal dreams Not known* Insomnia, agitation, aggression (see section 4.4)
Nervous system disorders Common Dizziness Not known* Serotonin syndrome, Headache
Eye disorders Rare Mydriasis (which may lead to acute narrow angle glaucoma - see section 4.4)
Vascular disorders Uncommon Flushing Not known* Haemorrhage (including contusion, ecchymosis, epistaxis, gastrointestinal or vaginal bleeding)
Gastrointestinal disorders Very common Nausea Common Diarrhoea, Constipation, Vomiting

In clinical studies, no patient ingested more than 75 mg BRINTELLIX on a single occasion. The clinical studies included subjects who were administered 40 to 75 mg. Ingestion of BRINTELLIX in this dose range caused an aggravation of the following adverse reactions: nausea, postural dizziness, diarrhoea, abdominal discomfort, generalised pruritus, somnolence and flushing. Post-marketing experience mainly concerns BRINTELLIX overdoses of up to 80 mg. The most frequently reported symptoms were nausea and vomiting. There is limited experience with BRINTELLIX overdoses above 80 mg. Following dosages several fold higher than the therapeutic dose range, events of seizure and serotonin syndrome have been reported. Management of overdose should consist of treating clinical symptoms and relevant monitoring. Medical follow-up in a specialised environment is recommended.