Vorellix Tablets

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

Posology
The starting and recommended dose of VORELLIX 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.

VORELLIX can be taken without regard to meals. After the depressive symptoms resolve, treatment for at least 6 months is recommended for consolidation of the anti-depressive response.

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

Special populations
Elderly patients
The safety and efficacy of VORELLIX 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.

Renal Impairment
No dose adjustment is needed for patients with renal impairment or for patients with end-stage renal disease. However, caution should be exercised when treating patients with severe renal insufficiency.

Hepatic Impairment
No dose adjustment is needed for patients with mild or moderate hepatic impairment. VORELLIX has not been studied in patients with severe hepatic impairment and caution should be exercised when prescribing to these patients.

Cytochrome P450 Inhibitors
Depending on individual patient response, a lower dose of VORELLIX may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to VORELLIX treatment.

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

Paediatric population
The safety and efficacy of VORELLIX in children and adolescents aged less than 18 years have not been established. No data are available.

Method of administration
VORELLIX is for oral use. The film-coated tablets can be taken with or without food.

• Hypersensitivity to vortioxetine 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).

Paediatric population
VORELLIX is not recommended for the treatment of depression in patients aged less than 18 years since the safety and efficacy of VORELLIX 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) may be 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 continues until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment with VORELLIX, 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 VORELLIX. In adult patients with psychiatric disorders, an increased risk of suicidal behaviour with antidepressants, in patients less than 25 years old may be seen. Close supervision of patients and in particular those at high risk should accompany treatment with VORELLIX 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 VORELLIX. Therefore, VORELLIX should be introduced with caution in patients who have a history of seizures or in patients with unstable epilepsy. Treatment with VORELLIX 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 VORELLIX. The risk of SS or NMS is increased with concomitant use of serotonergic medicines (including 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 sections 4.3 and 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 VORELLIX should be discontinued immediately and symptomatic treatment should be initiated.

Hyponatremia
Hyponatremia, 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 hyponatremia. Discontinuation of VORELLIX should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Activation of hypomania or mania
VORELLIX 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.

Haemorrhage
Bleeding abnormalities, such as ecchymoses, purpura and other haemorrhagic events such as gastrointestinal or gynecological bleeding may occur with VORELLIX. Caution is advised in patients taking anticoagulants and /or medicines 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 VORELLIX and bupropion may result in a higher incidence of adverse reactions when bupropion is added to VORELLIX than when VORELLIX is added to bupropion. Depending on individual patient response, a lower dose of VORELLIX may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to VORELLIX treatment (see section 4.2 and 4.5).

Aggression/ agitation
Patients treated with antidepressants, including vortioxetine, may also experience feelings of aggression, anger, agitation and irritability. Patient's condition and disease status should be closely monitored. Patients (and caregivers of patients) should be alerted to seek medical advice, if aggressive/agitated behaviour emerges or aggravates.

Glaucoma
Mydriasis has been reported in association with use of antidepressants, including vortioxetine. This mydriatic effect has the potential to narrow the eye angle resulting in increased intraocular pressure and angle-closure glaucoma. Caution is advised when prescribing vortioxetine to patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma. VORELLIX contains mannitol which may have a laxative effect.

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).

Potential for other medicines to affect vortioxetine

Monoamine Oxidase Inhibitors (MAOIs)
Due to the risk of serotonin syndrome, VORELLIX is contraindicated in any combination with MAOIs. VORELLIX must not be initiated for at least 14 days after discontinuation of treatment with an MAOI. VORELLIX 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 VORELLIX. 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. pethidine, 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 serotonin syndrome (see section 4.4).

Medicines lowering the seizure threshold
Antidepressants with serotonergic effect including VORELLIX can lower the seizure threshold. Caution is advised when concomitantly using VORELLIX and other medicines 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 data available with concurrent administration of VORELLIX and ECT, therefore caution is advisable.

Cytochrome P450 inhibitors
The exposure to vortioxetine may increase by 2,3-fold for AUC when VORELLIX 10 mg/day is co-administered with bupropion (a strong CYP2D6 inhibitor) 150 mg twice daily for 14 days. The co-administration may result in a higher incidence of adverse reactions when bupropion is added to VORELLIX than when VORELLIX is added to bupropion. Depending on individual patient response, a lower dose of VORELLIX may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to VORELLIX treatment (see section 4.2). If VORELLIX 10 mg/ day is co-administered following 6 days of ketoconazole 400 mg/day (a CYP3A4/5 and P-glycoprotein inhibitor), a 1,3-fold increase in vortioxetine AUC may be observed. No dose adjustment is needed. If VORELLIX 10 mg/day is co-administered following 6 days of fluconazole 200 mg/day (a CYP2C9, CYP2C19 and CYP3A4/5 inhibitor), a 1,5-fold increase in AUC may be observed. No dose adjustment is needed. There may be no inhibitory effect of 40 mg single dose omeprazole (CYP2C19 inhibitor) on the multiple dose pharmacokinetics of VORELLIX (10 mg/day).

Cytochrome P450 inducers
If a single dose of VORELLIX 20 mg is co-administered following 10 days of rifampicin 600 mg/day (a broad Inducer of CYP isozymes), a 72 % decrease in AUC of vortioxetine may be 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 VORELLIX treatment (see section 4.2).

Aspirin
There may be no effect of multiple doses of aspirin 150 mg/day on multiple dose pharmacokinetics of VORELLIX 10 mg/day. Anticoagulants and antiplatelet medicines No significant effects may be observed in INR, prothrombin or plasma R-/S-warfarin values following co-administration of VORELLIX 10 mg/day for 14 days with stable doses of warfarin. Also, no significant inhibitory effect, on platelet aggregation may be observed if aspirin 150 mg/day is co-administered following 14 days of VORELLIX 10 mg/day administration. However, caution should be exercised when VORELLIX is combined with oral anticoagulants or antiplatelet medicines due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction (see section 4.4).

Alcohol
There may be no significant additional impairment in cognitive function for VORELLIX single doses of 20 and 40 mg following co-administration with a single dose of ethanol 0,6 g/kg. However, the combination with alcohol is not advisable.

Diazepam
There may be no significant impairment, in cognitive function for VORELLIX following co-administration of VORELLIX 10 mg/day with a single 10 mg dose of diazepam.

Oral contraceptives
There may be no significant effects in the levels of sex hormones following co-administration of VORELLIX 10 mg/day with a combined oral contraceptive (ethinyl estradiol 30 u03bcg/ levonorgestrel 150 u03bcg) 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 VORELLIX (10 mg/day for 14 days) was observed for the cytochrome P450 isozymes CYP2C19 (omeprazole, diazepam), CYP2C9 (warfarin), CYP3A4 /5 (ethinylestradiol), or CYP2B6 (bupropion). In a study, no inhibitory effect of VORELLIX 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 VORELLIX 10 mg/day for 14 days. However, there have been reports of enhanced effects when antidepressants with serotonergic effect such as VORELLIX have been given together with lithium or tryptophan, therefore concomitant use of VORELLIX with these medicines should be undertaken with caution.

Interference with urine screens
There have been reports of false positive results in urine enzyme immunoassays for methadone in patients who have taken vortioxetine. Caution should be exercised in the interpretation of positive urine screen results, and confirmation by an alternative analytical technique (e.g., chromatographic methods) should be considered.

Pregnancy
VORELLIXu2019s safety and efficacy in pregnant women has not been established. The following symptoms may occur in the new-born after maternal use of VORELLIX 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 new-born (PPHN). Although no studies have investigated the association of PPHN to VORELLIX treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).

Breastfeeding
The safety of VORELLIX in breastfeeding women has not been established. Vortioxetine and/or its metabolites are excreted into the milk of lactating rats. It is expected that vortioxetine will be excreted into human milk. A risk to the suckling child cannot be excluded.

Fertility
The impact on human fertility has not been observed.

Patients should exercise caution when driving or operating hazardous machinery, especially when starting treatment with VORELLIX or when changing the dose.

The following adverse events have been reported:

Immune system disorders
Frequency unknown: Anaphylactic reaction

Metabolism and nutrition disorders
Frequent: Decreased appetite
Frequency unknown: Hyponatraemia

Psychiatric disorders
Frequent: Abnormal dreams
Less frequent: Bruxism
Frequency unknown: Insomnia, agitation, aggression

Nervous system disorders
Frequent: Dizziness
Frequency unknown: Serotonin Syndrome

Eye disorders
Less frequent: Mydriasis (which may lead to acute narrow angle glaucoma)

Vascular disorders
Less frequent: Flushing
Frequency unknown: Haemorrhage (including contusion, ecchymosis, epistaxis, gastrointestinal or vaginal bleeding)

Gastrointestinal disorders
Frequent: Nausea, diarrhoea, constipation, vomiting

Skin and subcutaneous tissue disorders
Frequent: Generalised pruritus
Less frequent: Night sweats
Frequency unknown: Angioedema, urticaria, rash

Description of selected adverse reaction
Elderly patients
For doses u2265 10 mg vortioxetine once daily, the withdrawal rate may be higher in patients u2265 65 years. For doses of 20 mg vortioxetine once daily, the incidences of nausea and constipation may be higher in patients aged u2265 65 years than in patients < 65 years (see section 4.4).

Sexual dysfunction: VORELLIX may cause sexual dysfunction especially at the 20 mg dose. Difficulties with satisfaction of orgasm and ease of sexual arousal may be the most prevalent manifestation.

Class effect: There is an increased risk of bone fractures in patients 50 years of age and older receiving a medicine from related pharmacological classes of antidepressants (SSRIs and TCAs).

There is limited experience with VORELLIX overdose. Ingestion of 40 to 75 mg VORELLIX may cause 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.