Zydus Vortioxetine Tablets

VORTIOXETINE ZYDUS is indicated for the treatment of major depressive disorder episodes and to reduce the risk of relapse.

Adults
VORTIOXETINE ZYDUS is for oral use in adults. The initial and recommended dose 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. After the depressive symptoms resolve, treatment for at least 6 months is recommended for consolidation of the antidepressive response. Patients can abruptly stop taking VORTIOXETINE ZYDUS without the need for a gradual reduction in dose.

Elderly patients
The safety and efficacy of VORTIOXETINE ZYDUS have been established in elderly patients. Caution is however advised when treating these patients. Treatment should be initiated with the minimum dose of 5 mg daily and, depending on the individual patient response, the dose may be increased to 10 mg daily. Data on doses exceeding 10 mg daily in the elderly are limited (see sections 4.4 and 5.2).

Renal impairment
No dose adjustment is required in patients with renal impairment or end-stage renal disease. However, when treating patients with severe renal insufficiency, caution is advised (see section 5.2).

Hepatic impairment
No dose adjustment is required in patients with mild or moderate hepatic impairment. VORTIOXETINE ZYDUS have not been studied in patients with severe hepatic impairment and caution is therefore advised when VORTIOXETINE ZYDUS is prescribed to these patients (see section 5.2).

Cytochrome P450 (CYP450) inhibitors
If strong CYP2D6 inhibitors (such as bupropion, quinidine, fluoxetine, paroxetine) are added to VORTIOXETINE ZYDUS treatment, a lower dose of VORTIOXETINE ZYDUS may be considered depending on individual patient response (see section 4.5).

Cytochrome P450 inducers
If a broad CYP450 inducer (such as rifampicin, carbamazepine, phenytoin) is added to VORTIOXETINE ZYDUS treatment, a dose adjustment of VORTIOXETINE ZYDUS may be considered depending on individual patient response (see section 4.5).

Paediatric patients
The safety and efficacy of VORTIOXETINE ZYDUS in children and adolescents under 18 years of age have not been established (see section 4.4).

Method of administration
VORTIOXETINE ZYDUS should be taken orally once a day, with or without food.

• Hypersensitivity to vortioxetine or to any of the excipients listed in section 6.1.
• Concomitant use of VORTIOXETINE ZYDUS with monoamine oxidase inhibitors (MAOIs) (see section 4.5).

Suicide/suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events), which persists until significant remission occurs. Improvement may not be present during the initial few weeks or more of treatment with VORTIOXETINE ZYDUS and patients should therefore be closely monitored until such improvement arises. General clinical experience demonstrates that the risk of suicide may increase in the initial stages of recovery. Patients are known to be at greater risk of suicidal thoughts or suicidal attempts when they present with a history of suicide-related events or displayed a significant degree of suicidal ideation prior to commencement of treatment. These patients should receive careful monitoring during treatment. When compared to placebo, an increased risk of suicidal behaviour with antidepressants was showed by a meta-analysis of placebo-controlled clinical studies of antidepressants in adult patients with psychiatric disorders and under the age of 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
There is a potential risk of seizures with the use of antidepressants including VORTIOXETINE ZYDUS. In patients with a history of seizures or unstable epilepsy, VORTIOXETINE ZYDUS should therefore be introduced with caution (see section 4.5). Treatment should be terminated in any patient who develops seizures or for whom an increase in the frequency of seizures occurs.

Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS)
Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS) are potentially life-threatening conditions and may occur with the use of VORTIOXETINE ZYDUS. An increased risk for SS or NMS results from the concurrent use of VORTIOXETINE ZYDUS and serotonergic-active substances (including triptans), medicines that impair the metabolism of serotonin (including MAOIs), antipsychotic medicines and other dopamine antagonists. Monitoring of patients for the development of signs and symptoms of SS or NMS is advised (see sections 4.3 and 4.5). The symptoms of SS may include mental status changes (such as agitation, hallucinations, coma), autonomic instability (such as tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (such as hyperreflexia, uncoordination) and/or gastrointestinal symptoms (such as nausea, vomiting, diarrhoea). If this occurs, treatment with VORTIOXETINE ZYDUS should be discontinued immediately and symptomatic treatment should be started.

Mania/hypomania
Caution is advised with VORTIOXETINE ZYDUS in patients with a history of mania or hypomania. The treatment should be discontinued in any patient entering a manic phase.

Aggression/agitation
Patients treated with antidepressants, including VORTIOXETINE ZYDUS, 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.

Haemorrhage
There have been reports of bleeding abnormalities, such as ecchymoses, purpura and other haemorrhagic events, such as gastrointestinal or gynaecological bleeding with the use of antidepressants with serotonergic effect, including VORTIOXETINE ZYDUS. Caution is advised with VORTIOXETINE ZYDUS in patients receiving anticoagulant treatment or other medicines known to exert an effect on platelet function (such as atypical antipsychotics and phenothiazines, most tricyclic antidepressants (TCAs), nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA)) (see section 4.5). Caution is also advised in patients with known bleeding disorders or tendencies.

Hyponatraemia
There have been reports of hyponatraemia, most likely due to inappropriate antidiuretic hormone secretion, with the use of antidepressants with serotonergic effect (SSRIs and SNRIs). Caution is therefore advised in patients at risk, such as the elderly, patients with liver cirrhosis or patients concomitantly treated with medicines known to cause hyponatraemia. In patients presenting with symptomatic hyponatraemia, the discontinuation of treatment with VORTIOXETINE ZYDUS should be considered and medical intervention introduced.

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 ZYDUS to patients with increased intraocular pressure, or those at risk of acute narrow-angle glaucoma.

Elderly patients
Caution is advised when treating elderly patients with doses higher than 10 mg once daily, as data on the use of VORTIOXETINE ZYDUS in elderly patients with major depressive episodes are limited (see sections 4.2, 4.8 and 5.2).

Renal or hepatic impairment
Given that subjects with renal or hepatic impairment are vulnerable and given that the data on the use of VORTIOXETINE ZYDUS in these subpopulations are limited, caution should be exercised when treating these patients (see sections 4.2 and 5.2).

Paediatric population
The safety and efficacy of vortioxetine, as in VORTIOXETINE ZYDUS, have not been established in patients under 18 years of age and the treatment of depression with VORTIOXETINE ZYDUS is therefore not recommended in this age group (see section 4.2). Clinical studies in children and adolescents treated with other antidepressants indicated that suicide-related behaviour (such as suicide attempt and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) are more frequently observed in these children than in those treated with a placebo.

VORTIOXETINE ZYDUS undergoes extensive hepatic metabolism, primarily through oxidation (catalysed by CYP2D6 and to a minor extent, CYP3A4/5 and CYP2C9) and subsequent glucuronic acid conjugation (see section 5.2).

MAOIs
The concomitant use of VORTIOXETINE ZYDUS with MAOIs should be avoided due to the risk of serotonin syndrome. Following the discontinuation of treatment with an MAOI, a waiting period of at least 14 days is required before treatment with VORTIOXETINE ZYDUS can be initiated. VORTIOXETINE ZYDUS must be discontinued for at least 14 days before treatment with an MAOI can be initiated.

Linezolid
The combination of vortioxetine with a MAOI, such as the antibiotic linezolid, is contraindicated (see section 4.3). If the combination proves essential, the added medicine should be given with minimum dosage and under close clinical monitoring for serotonin syndrome (see section 4.4).

Serotonergic medicines
Serotonin syndrome may result from the co-administration of VORTIOXETINE ZYDUS and medicines with serotonergic effect, such as pethidine, tramadol, sumatriptan and other triptans (see section 4.4).

Pregnancy
The use of VORTIOXETINE ZYDUS should be avoided during pregnancy, as the safety and efficacy in pregnant women have not been established. Studies in animals have indicated reproductive toxicity. The maternal use of a serotoninergic medicine, such as VORTIOXETINE ZYDUS, in the later stages of pregnancy may result in newborn symptoms, such as respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. In most cases, these complications were found to begin immediately or soon after delivery (less than 24 hours). These symptoms could be due to either the effects resulting from the discontinuation of the serotonergic medicine, or the excess of serotonergic activity. Data from epidemiological studies propose an increased risk of persistent pulmonary hypertension in the newborn (PPHN) when SSRIs are used in pregnancy, particularly in late pregnancy. The association of PPHN with VORTIOXETINE ZYDUS have not been studied and the potential risk should therefore not be neglected, considering the related mechanism of action of VORTIOXETINE ZYDUS (increase in serotonin concentrations).

Breastfeeding
The safety of VORTIOXETINE ZYDUS during breastfeeding has not been established. The excretion of VORTIOXETINE ZYDUS into human milk is however anticipated, as the excretion of vortioxetine and/or vortioxetine metabolites have been demonstrated by available animal data. The risk to the breastfeeding infant can therefore not be neglected.

Fertility
The effect of VORTIOXETINE ZYDUS on human fertility has not been studied.

Side effects such as dizziness may occur and impair the ability to drive or operate machines. Caution is advised before driving a vehicle or operating machinery until the effects of VORTIOXETINE ZYDUS are known, particularly at the start of treatment or following a dose adjustment.

Summary of the safety profile
The most frequent adverse reaction was nausea. The adverse reactions usually occur within the first two weeks of treatment. The following undesirable effects have been reported during clinical trials and post-marketing experience with vortioxetine
Immune system disorders
Frequency unknown: anaphylactic reaction*, angioedema*
Metabolism and nutrition disorders
Frequent: decreased appetite
Frequency unknown: hyponatraemia*
Psychiatric disorders
Frequent: abnormal dreams
Less frequent: bruxism
Frequency unknown: insomnia*, agitation*, aggression* (see section 4.4)
Nervous system disorders
Frequent: dizziness
Frequency unknown: serotonin syndrome*
Eye disorders
Less frequent: mydriasis (which may lead to acute narrow angle glaucoma (see section 4.4))
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: pruritis (including generalised pruritis)
Less frequent: night sweats
Frequency unknown: urticaria*, rash*

Symptoms of overdose
Experience with VORTIOXETINE ZYDUS overdose is limited. Clinical studies with vortioxetine indicate that doses of 40 u2013 75 mg can cause augmentation of adverse effects, such as nausea, postural dizziness, diarrhoea, abdominal discomfort, generalised pruritis, somnolence and flushing.

Management of overdose
In the event of an overdose, symptomatic measures should be employed and patients should be monitored as appropriate. It is advised that patients be medically followed-up in a specialised environment.