Brintellix · 4.6 Fertility, pregnancy and lactation · 1

HOS-096628 · has-adverse-reaction-information · PDF-Seite 28

Summary of the safety profile The most common adverse reaction was nausea. Tabulated list of adverse reactions Adverse reactions are listed below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). The list is based on information from clinical trials and post-marketing experience. 28  SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION Immune system disorders Not known * Anaphylactic reaction Endocrine disorders Not known * Hyperprolactinaemia, in some cases associated with galactorrhoea Metabolism and nutrition disorders Not known * Hyponatraemia Psychiatric disorders Common Abnormal dreams Uncommon Hallucinations Not known * Insomnia Agitation, aggression (see section 4.4) Nervous system disorders Common Dizziness Uncommon Tremor Not known * Serotonin Syndrome Headache Akathisia Bruxism Trismus Restless leg syndrome Eye disorders Rare Mydriasis (which may lead to acute narrow angle glaucoma - see section 4.4) Uncommon Blurred vision Vascular disorders Uncommon Flushing Not known * Haemorrhage (including contusion, ecchymosis, epistaxis, gas

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HOS-096622 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The most common adverse reaction was nausea. Tabulated list of adverse reactions Adverse reactions are listed below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). The list is based on information from clinical trials and post-marketing experience. 9  SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTION Immune system disorders Not known* Anaphylactic reaction Endocrine disorders Not known * Hyperprolactinaemia, in some cases associated with galactorrhoea Metabolism and nutrition disorders Not known * Hyponatraemia Psychiatric disorders Common Abnormal dreams Uncommon Hallucinations Not known * Insomnia Agitation, aggression (see section 4.4) Nervous system disorders Common Dizziness Uncommon Tremor Not known * Serotonin Syndrome, Headache, Akathisia, Bruxism, Trismus, Restless leg syndrome Eye disorders Uncommon Blurred vision Rare Mydriasis (which may lead to acute narrow angle glaucoma - see section 4.4) Vascular disorders Uncommon Flushing Not known* Haemorrhage (including contusion,

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HOS-096618 · has-contraindication-information · PDF-Seite 4

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).

HOS-096624 · has-contraindication-information · PDF-Seite 22

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).

HOS-096623 · has-indication-information · PDF-Seite 21

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

HOS-096617 · has-indication-information · PDF-Seite 3

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

HOS-096626 · has-interaction-information · PDF-Seite 24

Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by CYP2D6 and to a minor extent CYP3A4/5 and CYP2C9 (see section 5.2). 24 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 medicinal product should be given with minimum dosage and under close clinical monitoring for Serotonin Syndrome (see section 4.4). Irreversible, selective MAO-B inhibitor (selegiline, rasagiline) Although a lower risk of Serotonin Syndrome is expected with selective MAO-B inhibitors than with MAO-A inhibitors, the combination of vortioxetine with irreversible MAO-B inhibitors, such as selegiline or rasagiline should be administered with caution. Close monitoring for Serotonin Syndrome is necessary if used concomitantly (see section 4.4). Serotonergic medicinal products Co-administration of medicinal products with serotonergic effect e.g. opioids (including tramadol) and triptans (including sumatriptan) may lead to Serotonin Syndrome (see section 4.4). St. John’s wort Concomitant use of antidepressants with serotonergic effect and herbal remedies containing St. John’s wort (Hypericum perforatum) may result in a higher incidence of adverse reactions including Serotonin Syndrome (see section 4.4). Medicinal products lowering the seizure threshold Antidepressants with serotonergic effect can lower the seizure threshold. Caution is advised when conco

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HOS-096620 · has-interaction-information · PDF-Seite 6

Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by CYP2D6 and to a minor extent CYP3A4/5 and CYP2C9 (see section 5.2). Potential for other medicinal products to affect vortioxetine Irreversible non-selective MAOIs Due to the risk of serotonin syndrome, vortioxetine is contraindicated in any combination with irreversible non-selective MAOIs. Vortioxetine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible non-selective MAOI. Vortioxetine must be discontinued for at least 14 days before starting treatment with an irreversible non-selective MAOI (see section 4.3). Reversible, selective MAO-A inhibitor (moclobemide) The combination of vortioxetine with a reversible and selective MAO-A inhibitor, such as moclobemide, is contraindicated (see section 4.3). If the combination proves necessary, the added medicinal product should be given with minimum dosage and under close clinical monitoring for serotonin sSyndrome (see section 4.4). Reversible, non-selective MAOI (linezolid) The combination of vortioxetine with a weak reversible and non-selective MAOI, such as the antibiotic linezolid, is contraindicated (see section 4.3). If the combination proves necessary, the added medicinal product should be given with minimum dosage and under close clinical monitoring for serotonin syndrome (see section 4.4). Irreversible, selective MAO-B inhibitor (selegiline, rasagiline) Although a lower risk of serotonin syndrome is expected with selective MAO-B inhibitors than with MAO-A inhibitors, the combination of vortioxetine with irreversible MAO-B inhibitors, such as selegiline or rasagiline should be administered with caution. Close monitoring for serotonin syndrome is necessary if used concomitantly (see section 4.4). Serotonergic medicinal products Co-administration of medicinal products with serotonergic effect e.g.opioids (including tramadol) and triptans (including sumatriptan) may lead to serotonin syndrome (see section 4.4). St. John’s wort Concomitant use of antidepressants with serotonergic effect and herbal remedies containing St. John’s wort (Hypericum perforatum) may result in a higher incidence of adverse reactions including Serotonin Syndrome (see section 4.4). Medicinal products lowering the seizure threshold Antidepressants with serotonergic effect can lower the seizure threshold. Caution is advised when concomitantly using other medicinal products capable of loweri

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HOS-096621 · has-pregnancy-information · PDF-Seite 8

Pregnancy There are limited data from the use of vortioxetine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The following symptoms may occur in the newborn after maternal use of a serotonergic medicinal product in the later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either discontinuation effects or excess serotonergic activity. In the majority of instances, such complications began immediately or soon (<24 hours) after delivery. Epidemiological data suggest that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN with vortioxetine treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations). Brintellix should only be administered to pregnant women if the expected benefits outweigh the potential risk to the foetus. Observational data have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage following exposure to an SSRI or SNRI within the month prior to birth. Although no studies have investigated an association between vortioxetine treatment and postpartum haemorrhage, there is a potential risk, taking into account the related mechanism of action (See section 4.4) 8 Breast-feeding Limited published data show that Vortioxetine is excreted in small amounts into human breast milk with an estimated relative infant dose (RID) below 2%. No harmful, drug-associated effects have been observed in the infants. However, available clinical data are limited, and a risk to the breastfeeding child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Brintellix treatment taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Fertility studies in male and female rats showed no effect of vortioxetine on fertility, sperm quality or mating performance (see section 5.3). Human case reports with medicinal products from the relate

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HOS-096627 · has-pregnancy-information · PDF-Seite 27

Pregnancy There are limited data from the use of vortioxetine in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The following symptoms may occur in the newborn after maternal use of a serotonergic medicinal product in the later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either discontinuation effects or excess serotonergic activity. In the majority of instances, such complications began immediately or soon (<24 hours) after delivery. Epidemiological data suggest that the use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Although no studies have investigated the association of PPHN with vortioxetine treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations). Brintellix should only be administered to pregnant women if the expected benefits outweigh the potential risk to the foetus. Observational data have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage following exposure to an SSRI or SNRI within the month prior to birth. Although no studies have investigated an association between vortioxetine treatment and postpartum haemorrhage, there is a potential risk, taking into account the related mechanism of action (See section 4.4) Breast-feeding Limited published data show that Vortioxetine is excreted in small amounts into human breast milk with an estimated relative infant dose (RID) below 2%. No harmful, drug-associated effects have been observed in the infants. However, available clinical data are limited, and a risk to the breastfeeding child cannot be excluded. 27 A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Brintellix treatment taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Fertility studies in male and female rats showed no effect of vortioxetine on fertility, sperm quality or mating performance (see section 5.3). Human case reports with medicinal products from the relat

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HOS-096619 · has-warning-information · PDF-Seite 4

Use in paediatric population Brintellix should not be used in children and adolescents aged 7 to 17 years with MDD because efficacy has not been demonstrated (see section 5.1). In general , the adverse reaction profile of vortioxetine in children and adolescents was similar to that seen for adults except for a higher incidence of abdominal pain-related events, and a higher incidence of sucidal ideation in adolescents specifically, compared to adults (see section 4.8 and 5.1). In clinical studies in children and adolescents treated with antidepressants, suicide-related behaviour (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour, anger) were more frequently observed than in those treated with placebo. Suicide/suicidal thoughts or clinical worsening Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical studies of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo, in patients less than 25 years old. Close supervision of patients and in particular those at high risk should accompany treatment especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present. Seizures Seizures are a potential risk with antidepressants. Therefore, vortioxetine should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy (see section 4.5). Treatment should be discontinued in any patient who develops seizures or for whom there is an increase in seizure frequency. Serot

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HOS-096625 · has-warning-information · PDF-Seite 22

Use in paediatric population Brintellix should not be used in children and adolescents aged 7 to 17 years with (MDD because efficacy has not been demonstrated (see section 5.1). In general, the adverse reaction profile of vortioxetine in children and adolescents was similar to that seen for adults except for a higher 22 incidence of abdominal pain-related events, and a higher incidence of suicidal ideation in adolescents specifically, compared to adults (see section 4.8 and 5.1). In clinical studies in children and adolescents treated with antidepressants, suicide-related behaviour (suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour, anger) were more frequently observed than in those treated with placebo. Suicide/suicidal thoughts or clinical worsening Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo-controlled clinical studies of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo, in patients less than 25 years old. Close supervision of patients and in particular those at high risk should accompany treatment especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present. Seizures Seizures are a potential risk with antidepressants. Therefore, vortioxetine should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy (see section 4.5). Treatment should be discontinued in any patient who develops seizures o

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