Adco Vortioxetine Tablet

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

Posology
The starting and recommended dose of VORTIOXETINE ADCO is 10 mg once daily. Depending on the 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 treatment. A dose decrease may be considered for patients who do not tolerate higher doses.

After the depressive symptoms resolve, treatment for a least 6 months is recommended for consolidation of the anti-depressive response.

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

Special populations

Elderly patients
The safety and efficacy of VORTIOXETINE ADCO 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 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 ADCO has not been studied in patients with severe hepatic impairment and caution should be exercised when prescribing to these patients (see section 5.2).

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

Cytochrome P450 inhibitors
Depending on individual patient response, a lower dose of VORTIOXETINE ADCO may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to VORTIOXETINE ADCO treatment (see section 4.5).

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

Method of administration
VORTIOXETINE ADCO is for oral use in adults. VORTIOXETINE ADCO can be taken without regard to meals.

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
VORTIOXETINE ADCO is not recommended in patients aged less than 18 years for the treatment of depression since the safety and efficacy of vortioxetine have not been established in this age group (see section 4.2).

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. Patients should be closely monitored until improvement occurs, as improvement may not occur during the first few weeks or more of treatment with vortioxetine. 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 of age. Close supervision of patients and in particular those at high risk should accompany treatment with VORTIOXETINE ADCO 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 ADCO. Therefore, VORTIOXETINE ADCO 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.

Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS)
Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS), potentially life-threatening conditions, may occur with VORTIOXETINE ADCO. The risk of SS or NMS is increased with concomitant use of serotonergic-active substances (including triptans), medicines that impair the 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 include autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhoea), mental status changes (e.g., agitation, hallucinations, coma) and/or neuromuscular aberrations (e.g., hyperreflexia, incoordination). If this occurs, treatment with VORTIOXETINE ADCO should be discontinued immediately and symptomatic treatment should be initiated.

Hyponatraemia
Hyponatraemia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported less frequently with the use of antidepressants with serotonergic effect (SSRIs, SNRIs). Caution should be exercised in patients at risk, such as the elderly, patients with cirrhosis of the liver or patients concomitantly treated with medicines known to cause hyponatraemia. Discontinuation of VORTIOXETINE ADCO should be considered in patients with symptomatic hyponatraemia and appropriate medical intervention should be instituted.

Activation of hypomania or mania
VORTIOXETINE ADCO 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, have been reported less frequently with the use of antidepressants with serotonergic effect, including VORTIOXETINE ADCO. 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), aspirin (acetylsalicylic acid u2013 ASA)] (see section 4.5) and in patients with known bleeding tendencies/disorders.

Co-administration with cytochrome P450 inhibitors
Co-administration of VORTIOXETINE ADCO and bupropion resulted in a higher incidence of adverse reactions when bupropion was added to VORTIOXETINE ADCO than when VORTIOXETINE ADCO as added to bupropion (see section 4.5).

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

Irreversible non-selective MAOIs
Due to the risk of serotonin syndrome, VORTIOXETINE ADCO is contraindicated in any combination with irreversible non-selective MAOIs (see section 4.3). VORTIOXETINE ADCO must not be initiated for at least 14 days after discontinuation of treatment with an irreversible nonselective MAOI. VORTIOXETINE ADCO 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 ADCO with a reversible and selective MAO-A inhibitor, such as moclobemide, is contraindicated (see section 4.3). If the combination proves necessary, the added medicine 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 ADCO 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 medicine 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 ADCO 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 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 VORTIOXETINE ADCO, can lower the seizure threshold. Caution is advised when concomitantly using VORTIOXETINE ADCO and other medicines capable of lowering the seizure threshold [e.g., antidepressants (tricyclics, SSRIs, SNRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquine, bupropion, tramadol] (see section 4.4).

ECT (electroconvulsive therapy)
There is no clinical experience with concurrent administration of VORTIOXETINE ADCO and ECT, therefore caution is advisable.

CYP2D6 inhibitors
The exposure to vortioxetine increased 2,3-fold for area under the curve (AUC) when vortioxetine (as in VORTIOXETINE ADCO) 10 mg/day was co-administered with bupropion (a strong CYP2D6 inhibitor 150 mg twice daily) for 14 days in healthy subjects. Co-administration resulted in a higher incidence of adverse reactions when bupropion was added to vortioxetine (as in VORTIOXETINE ADCO) than when vortioxetine (as in VORTIOXETINE ADCO) was added to bupropion. Depending on individual patient response, a lower dose of VORTIOXETINE ADCO may be considered if a strong CYP2D6 inhibitor (e.g., bupropion, quinidine, fluoxetine, paroxetine) is added to VORTIOXETINE ADCO treatment (see section 4.2).

CYP3A4 inhibitors and CYP2C9, and CYP2C19 inhibitors
When vortioxetine (as in VORTIOXETINE ADCO) was co-administered following 6 days of ketoconazole 400 mg/day (a CYP3A4/5 and P-glycoprotein inhibitor) or following 6 days of fluconazole 200 mg/day (a CYP2C9, CYP2C19, and CYP3A4/5 inhibitor) in healthy subjects, a 1,3-fold and 1,5-fold increase, respectively, in vortioxetine 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 vortioxetine (as in VORTIOXETINE ADCO) in healthy subjects.

Interactions in CYP2D6 poor metabolisers
Co-administration of strong inhibitors of CYP3A4 (such as itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, conivaptan and many of the HIV protease inhibitors) and inhibitors of CYP2C9 (such as fluconazole and amiodarone) to CYP2D6 poor metabolisers (see section 5.2) has not been investigated specifically, but it is anticipated that it will lead to a more marked increased exposure of vortioxetine (as in VORTIOXETINE ADCO) in these patients as compared to the moderate effect described above. Depending on individual patient response, a lower dose of VORTIOXETINE ADCO may be considered if a strong inhibitor of CYP3A4 or CYP2C9 is co-administered in CYP2D6 poor metabolisers.

Cytochrome P450 inducers
When a single dose of 20 mg vortioxetine (as in VORTIOXETINE ADCO) was co-administered following 10 days of rifampicin 600 mg/day (a broad inducer of CYP isozymes) in 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 VORTIOXETINE ADCO treatment (see section 4.2).

Alcohol
No effect on the pharmacokinetics of vortioxetine or ethanol and no significant impairment, relative to placebo, in cognitive function were observed when vortioxetine (as in VORTIOXETINE ADCO) in a single dose of 20 mg or 40 mg was co-administered with a single dose of ethanol (0,6 g/kg) in healthy subjects. However, alcohol intake is not advisable during antidepressant treatment.

Acetylsalicylic acid (Aspirin)
No effect of multiple doses of acetylsalicylic acid 150 mg/day on the multiple-dose pharmacokinetics of vortioxetine (as in VORTIOXETINE ADCO) was observed in healthy subjects.

Pregnancy
There are limited data from the use of vortioxetine in pregnant women. The safety and efficacy of VORTIOXETINE ADCO in pregnant women has not been established. Newborn: The following symptoms may occur in the newborn after maternal use of VORTIOXETINE ADCO 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 ADCO treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).

Breastfeeding
Available data in animals have shown excretion of vortioxetine/ vortioxetine metabolites into milk. It is expected that vortioxetine will be excreted into human milk. The safety of VORTIOXETINE ADCO in breastfeeding women has not been established.

Fertility
Fertility studies in male and female rats showed no effect of vortioxetine on fertility, sperm quality or mating performance. Human case reports with medicines from the related pharmacological class of antidepressants (SSRIs) have shown an effect on sperm quality that is reversible. Impact on human fertility has not been observed so far.

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

a. Summary of the safety profile
The most common adverse reaction was nausea.

b. Tabulated summary of adverse reactions

SYSTEM ORGAN CLASS FREQUENCY ADVERSE REACTIONS
Immune system disorders Frequency not known* Anaphylactic reaction.
Metabolism and nutrition disorders Frequency not known* Decreased appetite, hyponatraemia.
Psychiatric disorders Frequent Abnormal dreams.
Less frequent Bruxism.
Nervous system disorders Frequent Dizziness.
Frequency not known* Serotonin syndrome.
Vascular disorders Less frequent Flushing.
Frequency not known* Ecchymosis, epistaxis, haemorrhage (including contusion, gastrointestinal or vaginal bleeding).
Gastrointestinal disorders Frequent Constipation, diarrhoea, nausea, vomiting.
Skin and subcutaneous tissue disorders Frequent Pruritus, including pruritus generalised.
Less frequent Night sweats.
Frequency not known* Angioedema, rash, urticaria.

* Based on post-marketing cases

c. Description of selected adverse reactions

Nausea
Nausea was 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. Gastrointestinal adverse reactions, such as nausea, occurred more frequently in women than men.

Elderly patients
For doses u2265 10 mg vortioxetine (as in VORTIOXETINE ADCO) once daily, the withdrawal rate from the studies was higher in patients aged u2265 65 years. For doses of 20 mg vortioxetine (as in VORTIOXETINE ADCO) once daily, the incidences of nausea and constipation were higher in patients aged u2265 65 years (42 % and 15 %, respectively) than in patients aged < 65 years (27 % and 4 %, respectively) (see section 4.4).

Sexual dysfunction
Sexual dysfunction (i.e. difficulties with satisfaction of orgasm and ease of sexual arousal) was assessed using the Arizona Sexual Experience Scale (ASEX). Doses of 5 to 15 mg showed no difference to placebo. However, the 20 mg dose of vortioxetine (as in VORTIOXETINE ADCO) was associated with an increase in sexual dysfunction (treatment-emergent sexual dysfunction (TESD)) (see section 5.1).

Class effect
Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving medicine from related pharmacological classes of antidepressants (SSRIs or TCAs). The mechanism behind this risk is unknown, and it is not known if this risk is also relevant for VORTIOXETINE ADCO.

d. Paediatric population
No information.

e. Other special population(s)
No information.

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 professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

There is limited experience with VORTIOXETINE ADCO overdosage. In clinical studies, no patient ingested more than 75 mg vortioxetine (as in VORTIOXETINE ADCO) on a single occasion. Ingestion of vortioxetine in clinical trials in the dose range of 40 mg to 75 mg has caused 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.