Aspen Vortioxetine Tablets

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

Posology

Adults

VORTIOXETINE ASPEN is for use in adults. The starting and recommended dose of VORTIOXETINE ASPEN 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. VORTIOXETINE ASPEN 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. Patients being treated with VORTIOXETINE ASPEN can abruptly stop taking VORTIOXETINE ASPEN without the need for a gradual reduction in dose.

Special populations

Elderly population

The safety and efficacy of VORTIOXETINE ASPEN 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 (see section 5.2).

Hepatic impairment

No dose adjustment is needed for patients with mild or moderate hepatic impairment. VORTIOXETINE ASPEN has not been studied in patients with severe hepatic impairment and caution should be exercised when prescribing to these patients (see section 5.2).

Cytochrome P450 inhibitors

Depending on individual patient response, a lower dose of VORTIOXETINE ASPEN may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to VORTIOXETINE ASPEN treatment (see section 4.5).

Cytochrome P450 inducers

Depending on individual patient response, a dose adjustment of VORTIOXETINE ASPEN may be considered if a broad cytochrome P450 inducer (e.g. rifampicin, carbamazepine, phenytoin) is added to VORTIOXETINE ASPEN treatment (see section 4.5).

Paediatric population

The safety and efficacy of VORTIOXETINE ASPEN in children and adolescents aged less than 18 years have not been established. No data is available.

Method of administration

For oral administration. The film-coated tablets can be taken with or without food.

VORTIOXETINE ASPEN is contraindicated in:

• Patients with hypersensitivity to vortioxetine or to any excipients in VORTIOXETINE ASPEN (see section 6.1).
• Concomitant use of VORTIOXETINE ASPEN with monoamine oxidase inhibitors (MAOIs) (see section 4.5).

Use in paediatric population

VORTIOXETINE ASPEN is not recommended for the treatment of depression in patients aged less than 18 years since the safety and efficacy of VORTIOXETINE ASPEN 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 and 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 VORTIOXETINE ASPEN, 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 VORTIOXETINE ASPEN. 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 VORTIOXETINE ASPEN 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 VORTIOXETINE ASPEN. Therefore, VORTIOXETINE ASPEN should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy. Treatment with VORTIOXETINE ASPEN should be discontinued in any patient who develops seizures or where there is an increase in seizure frequency.

Serotonin syndrome and neuroleptic malignant syndrome

Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS), potentially life-threatening conditions, may occur with VORTIOXETINE ASPEN. 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 VORTIOXETINE ASPEN 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 medicines known to cause hyponatraemia. Discontinuation of VORTIOXETINE ASPEN should be considered in patients with symptomatic hyponatraemia and appropriate medical intervention should be instituted.

Activation of hypomania or mania

VORTIOXETINE ASPEN 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 gynaecological bleeding may occur with VORTIOXETINE ASPEN. 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.

Risk of postpartum haemorrhage

Literature has shown evidence of a risk of postpartum haemorrhage associated with the use of selective serotonin reuptake inhibitors (SSRIs), such as VORTIOXETINE ASPEN, and selective non-serotonin reuptake inhibitors (SNRIs). The observed relative risk demonstrated point estimates signifying an increasing risk when the use of an antidepressant is closer to the date of delivery.

Vortioxetine, as contained in VORTIOXETINE ASPEN 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, VORTIOXETINE ASPEN is contraindicated in any combination with MAOIs. VORTIOXETINE ASPEN must not be initiated for at least 14 days after discontinuation of treatment with an MAOI. VORTIOXETINE ASPEN 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 VORTIOXETINE ASPEN. 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. 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 VORTIOXETINE ASPEN can lower the seizure threshold. Caution is advised when concomitantly using VORTIOXETINE ASPEN 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 clinical experience with concurrent administration of VORTIOXETINE ASPEN and ECT, therefore caution is advisable.

Cytochrome P450 inhibitors

The exposure to vortioxetine increased 2,3-fold for AUC when Vortioxetine 10 mg Aspen/day was co-administered with bupropion (a strong CYP2D6 inhibitor) 150 mg twice daily for 14 days in 44 healthy patients. The co-administration resulted in a higher incidence of adverse reactions when bupropion was added to VORTIOXETINE ASPEN than when VORTIOXETINE ASPEN was added to bupropion. Depending on individual patient response, a lower dose of VORTIOXETINE ASPEN may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to VORTIOXETINE ASPEN treatment (see section 4.2). When VORTIOXETINE 10 mg ASPEN/day was co-administered following 6 days of ketoconazole 400 mg/day (a CYP3A4/5 and P-glycoprotein inhibitor) in 17 healthy patients, a 1,3-fold increase in vortioxetine AUC was observed. No dose adjustment is needed. When VORTIOXETINE 10 mg ASPEN/day was co-administered following 6 days of fluconazole 200 mg/day (a CYP2C9, CYP2C19 and CYP3A4/5 inhibitor) in 16 healthy patients, a 1,5-fold increase in AUC was observed. No dose adjustment is needed.

Cytochrome P450 inducers

When a single dose of VORTIOXETINE 20 mg ASPEN was co-administered following 10 days of rifampicin 600 mg/day (a broad inducer of CYP isozymes) in 14 healthy patients, 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 ASPEN treatment (see section 4.2).

Aspirin

No effect of multiple doses of aspirin 150 mg/day on multiple dose pharmacokinetics of VORTIOXETINE 10 mg ASPEN/day was observed in 28 healthy patients.

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 VORTIOXETINE 10 mg ASPEN/day for 14 days with stable doses of warfarin in 52 healthy patients. 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 VORTIOXETINE 10 mg ASPEN/day administration in 28 healthy patients. However, caution should be exercised when VORTIOXETINE ASPEN 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

No significant additional impairment, relative to placebo, in cognitive function using a battery of neuropsychological tests was observed for VORTIOXETINE ASPEN single doses of 20 and 40 mg following co-administration with a single dose of ethanol 0,6 g/kg in 55 healthy patients. 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 VORTIOXETINE ASPEN following co-administration of Vortioxetine 10 mg Aspen/day with a single 10 mg dose of diazepam in 32 healthy patients.

Oral contraceptives

No significant effects, relative to placebo, were observed in the levels of sex hormones following co-administration of VORTIOXETINE 10 mg ASPEN/day with a combined oral contraceptive (ethinyl oestradiol 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 Pharmacokinetic properties). No inhibitory effect of VORTIOXETINE ASPEN (10 mg/day for 14 days) was observed in healthy patients for the cytochrome P450 isozymes CYP2C19 (omeprazole, diazepam), CYP2C9 (warfarin), CYP3A4/5 (ethinyl oestradiol), or CYP2B6 (bupropion). In a medicine interaction study in healthy patients, no inhibitory effect of VORTIOXETINE 10 mg ASPEN/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 coadministration with VORTIOXETINE 10 mg ASPEN/day for 14 days in 16 healthy patients. However, there have been reports of enhanced effects when antidepressants with serotonergic effect such as VORTIOXETINE ASPEN have been given together with lithium or tryptophan, therefore concomitant use of VORTIOXETINE ASPEN with these medicines should be undertaken with caution.

Pregnancy

VORTIOXETINE ASPENu2019s safety and efficacy in pregnant women has not been established. The following symptoms may occur in the newborn after maternal use of VORTIOXETINE ASPEN 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 VORTIOXETINE ASPEN treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).

Breastfeeding

The safety of VORTIOXETINE ASPEN in breastfeeding women has not been established. Vortioxetine and/or its metabolites are excreted into the milk of lactating rats.

Fertility

Fertility studies in male and female rats showed no effect of vortioxetine on fertility, sperm quality or mating performance. Human case reports with other medicines from related pharmacological class of antidepressants (SSRIs) have been shown.

VORTIOXETINE ASPEN has no or negligible influence on the ability to drive and use machines. However, as adverse reactions such as dizziness have been reported, patients should exercise caution when driving or operating hazardous machinery, especially when starting treatment with vortioxetine or when changing the dose.

a) 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.

b) Tabulated list of adverse reactions

System organ class

Frequent

Less frequent

• Metabolism and nutrition disorders
• Decreased appetite
• Psychiatric disorders
• Abnormal dreams
• Bruxism
• Nervous system disorders
• Dizziness
• Vascular disorders
• Flushing
• Gastrointestinal disorders
• Nausea, diarrhoea, constipation, vomiting
• General disorders and administrative site conditions
• Generalised pruritus
• Night sweats

c) Post-marketing adverse reactions

System organ class

Frequency unknown (cannot be estimated from the available data)

• Infections and infestations
• Anaphylactic reaction
• Immune system disorders
• Angioedema
• Metabolism and nutrition disorders
• Hyponatraemia
• Nervous system disorders
• Serotonin Syndrome
• Vascular disorders
• Haemorrhage (including contusion, ecchymosis, epistaxis, gastrointestinal or vaginal bleeding), risk of postpartum haemorrhage
• Skin and subcutaneous tissue disorders
• Urticaria, rash

d) Description of selected adverse reactions

Sexual dysfunction VORTIOXETINE ASPEN may cause sexual dysfunction especially at the 20 mg dose. The following manifestations, i.e. difficulties with satisfaction of orgasm and ease of sexual arousal, as measured using the Arizona Sexual Experience Scale (ASEX), were the most prevalent for VORTIOXETINE ASPEN.

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 medicine from related pharmacological classes of antidepressants (SSRIs and TCAs). The mechanism behind this risk is unknown, and it is not known to what extent this risk is also relevant for VORTIOXETINE ASPEN.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to: SAHPRA: https://www.sahpra.org.za/health-products-vigilance/ Aspen Pharmacare: E-mail: [email protected] Tel: 0800 118 088

Symptoms

There is limited experience with VORTIOXETINE ASPEN overdose. In clinical studies, no patient ingested more than 75 mg VORTIOXETINE ASPEN on a single occasion. The clinical studies included patients who were administered 40 to 75 mg. Ingestion of VORTIOXETINE ASPEN in this dose range caused an aggravation of the following adverse reactions: nausea, postural dizziness, diarrhoea, abdominal discomfort, generalised pruritus, somnolence and flushing.

Treatment

Management of overdose should consist of treating clinical symptoms and relevant monitoring. Medical follow-up in a specialised environment is recommended.