Brivor Tablets

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

Posology
The starting and recommended dose of BRIVOR 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 anti-depressive response. Patients being treated with BRIVOR can abruptly stop taking BRIVOR without the need for a gradual reduction in dose.

Special populations
Elderly patients
The safety and efficacy of BRIVOR 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. BRIVOR 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 BRIVOR may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to BRIVOR treatment (see section 4.5).

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

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

Method of administration
The film-coated tablets are for oral use and can be taken with or without food. Missed dose: Doctors should advise patients who forget to take BRIVOR to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose.

• hypersensitivity to vortioxetine or to any of the ingredients of BRIVOR listed in section 6.1
• concomitant use with monoamine oxidase inhibitors (MAOIs) selective MAO-A inhibitors (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). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment with BRIVOR, 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 BRIVOR. 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 BRIVOR 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 BRIVOR. Therefore, BRIVOR should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy. Treatment with BRIVOR 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 BRIVOR. 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 4.4). 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 BRIVOR 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 medications known to cause hyponatraemia. Discontinuation of BRIVOR should be considered in patients with symptomatic hyponatraemia and appropriate medical intervention should be instituted.

Activation of hypomania or mania
BRIVOR 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 BRIVOR. Caution is advised in patients taking anticoagulants and/or medicinal products 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 vortioxetine and bupropion resulted in a higher incidence of adverse reactions when bupropion was added to vortioxetine than when vortioxetine was added to bupropion. Depending on individual patient response, a lower dose of BRIVOR may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to BRIVOR treatment (see sections 4.2 and 4.5).

Elderly
Data on the use of BRIVOR in elderly patients with major depressive episodes are limited. Therefore, caution should be exercised when treating patients u2265 65 years of age with doses higher than 10 mg BRIVOR once daily (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 BRIVOR in these sub-populations are limited, caution should be exercised when treating these patients (see section 4.2 and 5.2).

BRIVOR contains mannitol which may cause a mild laxative effect.

Vortioxetine, as contained in BRIVOR, 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).

Contraindicated combinations:

• Monoamine Oxidase Inhibitors (MAOIs)
  Due to the risk of serotonin syndrome, BRIVOR is contraindicated in any combination with MAOIs. BRIVOR must not be initiated for at least 14 days after discontinuation of treatment with an MAOI. BRIVOR must be discontinued for at least 14 days before starting treatment with an MAOI (see section 4.3).
• Reversible, selective MAO-A inhibitor (moclobemide)
  The combination of BRIVOR 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).
• Linezolid (MAOIs)
  The antibiotic linezolid is a weak MAOI and should not be given to patients treated with BRIVOR (see section 4.3). Close monitoring for serotonin syndrome is necessary if used concomitantly (see section 4.4).

Potential for other medicines to affect BRIVOR:

Serotonergic medicines
Co-administration of antidepressants and other medicines with 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).

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 BRIVOR 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).

Medicines lowering the seizure threshold
Antidepressants with serotonergic effect including BRIVOR can lower the seizure threshold. Caution is advised when concomitantly using BRIVOR and other medicines capable of lowering the seizure threshold (e.g. antidepressants (tricyclics, SSRIs, SNRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquine, bupropion and tramadol (see section 4.4).

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

Cytochrome P450 inhibitors

CYP2D6 inhibitor
The exposure to vortioxetine increased 2,3-fold for AUC when BRIVOR 10 mg/day was co-administered with bupropion (a strong CYP2D6 inhibitor) 150 mg twice daily for 14 days in 44 healthy subjects. The co-administration resulted in a higher incidence of adverse reactions when bupropion was added to BRIVOR than when BRIVOR was added to bupropion. Depending on individual patient response, a lower dose of BRIVOR may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to BRIVOR treatment (see section 4.2).

Cytochrome P450 inducers
When a single dose of 20 mg BRIVOR 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 BRIVOR treatment (see section 4.2).

Aspirin
No effect of multiple doses of aspirin 150 mg/day on multiple dose pharmacokinetics of BRIVOR 10 mg/ day was observed in healthy subjects.

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

Pregnancy
BRIVORu2019s safety and efficacy in pregnant women has not been established. The following symptoms may occur in the new-born after maternal use of BRIVOR 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 BRIVOR treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).

Breastfeeding
The safety of BRIVOR in breastfeeding women has not been established. Available data in animals have shown excretion of vortioxetine/vortioxetine metabolites in milk. It is expected that BRIVOR will be excreted into human milk (see section 5.3). A risk to the breastfeeding child cannot be excluded.

Fertility
Fertility studies in male and female rats showed no effect of vortioxetine, as in BRIVOR, on fertility, sperm quality or mating performance (see section 5.3). 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.

BRIVOR 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 BRIVOR 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 summary of adverse reactions

c) Description of selected adverse reactions
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.

d) Other special populations
Elderly patients
For doses u226510 mg BRIVOR once daily, the withdrawal rate from the studies was higher in patients aged u2265 65 years. For doses of 20 mg BRIVOR once daily, the incidences of nausea and constipation were higher in patients aged u2265 65 years (than in patients aged < 65 years (see section 4.4).

Sexual Dysfunction
BRIVOR 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. (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 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 BRIVOR.

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 via the online service for adverse drug reaction reporting by following the link: https://www.sahpra.org.za/Publications/Index/8 An email can be sent directly to the company, [email protected] to ensure safety of the product.

There is limited experience with BRIVOR overdose. In clinical studies, no patient ingested more than 75 mg vortioxetine, as in BRIVOR on a single occasion. The clinical studies included subjects who were administered 40 to 75 mg and ingestion of BRIVOR in this dose range may cause an aggravation of the following signs and symptoms: Nausea, postural dizziness, diarrhoea, abdominal discomfort, generalised pruritus, somnolence and flushing.

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