Source: Health Products Regulatory Authority (ZA) Publisher: Adcock Ingram Limited, 1 New Road, Erand Gardens, Midrand, 1685, Customer Care: 0860/ADCOCK (232625)
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).
TRINTOGEN 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).
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 TRINTOGEN 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 are a potential risk with antidepressants, including TRINTOGEN. Therefore, TRINTOGEN 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), potentially life-threatening conditions, may occur with TRINTOGEN. 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 TRINTOGEN should be discontinued immediately and symptomatic treatment should be initiated.
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 TRINTOGEN should be considered in patients with symptomatic hyponatraemia and appropriate medical intervention should be instituted.
TRINTOGEN should be used with caution in patients with a history of mania/hypomania and should be discontinued in any patient entering a manic phase.
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 TRINTOGEN. 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 – ASA)] (see section 4.5) and in patients with known bleeding tendencies/disorders.
Co-administration of TRINTOGEN and bupropion resulted in a higher incidence of adverse reactions when bupropion was added to TRINTOGEN than when TRINTOGEN as added to bupropion (see section 4.5).
Depending on individual patient response, a lower dose of TRINTOGEN may be considered if strong CYP2D6 inhibitors (e.g. bupropion, quinidine, fluoxetine, paroxetine) are added to TRINTOGEN treatment (see sections 4.2 and 4.5).
Data on the use of vortioxetine (as in TRINTOGEN) in elderly patients with major depressive episodes are limited. Therefore, caution should be exercised when treating patients ≥65 years of age with doses higher than 10 mg vortioxetine once daily (see sections 4.2, 4.8 and 5.2).
Limited data are available for patients with severe renal impairment. Caution should therefore be exercised (see section 5.2).
Vortioxetine (as in TRINTOGEN) has not been studied in patients with severe hepatic impairment and caution should be exercised when treating these patients (see section 5.2).
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).
Due to the risk of serotonin syndrome, TRINTOGEN is contraindicated in any combination with irreversible non-selective MAOIs (see section 4.3). TRINTOGEN must not be initiated for at least 14 days after discontinuation of treatment with an irreversible nonselective MAOI. TRINTOGEN must be discontinued for at least 14 days before starting treatment with an irreversible non-selective MAOI (see section 4.3).
The combination of TRINTOGEN 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).
The combination of TRINTOGEN 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).
Although a lower risk of serotonin syndrome is expected with selective MAO-B inhibitors than with MAO-A inhibitors, the combination of TRINTOGEN 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).
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).
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).
Antidepressants with serotonergic effect, including TRINTOGEN, can lower the seizure threshold. Caution is advised when concomitantly using TRINTOGEN 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).
There is no clinical experience with concurrent administration of TRINTOGEN and ECT, therefore caution is advisable.
The exposure to vortioxetine increased 2,3-fold for area under the curve (AUC) when vortioxetine (as in TRINTOGEN) 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 TRINTOGEN) than when vortioxetine (as in TRINTOGEN) was added to bupropion. Depending on individual patient response, a lower dose of TRINTOGEN may be considered if a strong CYP2D6 inhibitor (e.g., bupropion, quinidine, fluoxetine, paroxetine) is added to TRINTOGEN treatment (see section 4.2).
When vortioxetine (as in TRINTOGEN) 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 TRINTOGEN) in healthy subjects.
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 TRINTOGEN) in these patients as compared to the moderate effect described above.
Depending on individual patient response, a lower dose of TRINTOGEN may be considered if a strong inhibitor of CYP3A4 or CYP2C9 is co-administered in CYP2D6 poor metabolisers.
When a single dose of 20 mg vortioxetine (as in TRINTOGEN) 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 TRINTOGEN treatment (see section 4.2).
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 TRINTOGEN) 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.
No effect of multiple doses of acetylsalicylic acid 150 mg/day on the multiple-dose pharmacokinetics of vortioxetine (as in TRINTOGEN) was observed in healthy subjects.
No significant effects, relative to placebo, were observed in INR, prothrombin or plasma R-/S-warfarin values following co-administration of multiple doses of vortioxetine with stable doses of warfarin in healthy subjects. Also, no significant inhibitory effect, relative to placebo, on platelet aggregation or pharmacokinetics of acetylsalicylic acid or salicylic acid was observed when acetylsalicylic acid 150 mg/day was co-administered following multiple doses of vortioxetine (as in TRINTOGEN) administration in healthy subjects. However, caution should be exercised when TRINTOGEN 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).
In vitro, vortioxetine (as in TRINTOGEN) did not show any relevant potential for inhibition or induction of cytochrome P450 isozymes (see section 5.2).
Following multiple doses of vortioxetine, no inhibitory effect was observed in healthy subjects for the cytochrome P450 isozymes CYP2C19 (omeprazole, diazepam), CYP3A4/5 (ethinyl estradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (tolbutamide, S-warfarin), CYP1A2 (caffeine) or CYP2D6 (dextromethorphan).
No pharmacodynamic interactions were observed. No significant impairment, relative to placebo, in cognitive function was observed for vortioxetine following co-administration with a single 10 mg dose of diazepam. No significant effects, relative to placebo, were observed in the levels of sex hormones following co-administration of vortioxetine with a combined oral contraceptive (ethinyl estradiol 30 μg/levonorgestrel 150 μg).
No clinically relevant effect was observed during steady-state lithium exposure following co-administration with multiple doses of vortioxetine in healthy subjects. However, there have been reports of enhanced effects when antidepressants with serotonergic effect have been given together with lithium or tryptophan; therefore, concomitant use of TRINTOGEN with these medicines should be undertaken with caution.
There are limited data from the use of vortioxetine in pregnant women.
The safety and efficacy of TRINTOGEN in pregnant women has not been established.
The following symptoms may occur in the newborn after maternal use of TRINTOGEN 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 TRINTOGEN treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).
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 TRINTOGEN in breastfeeding women has not been established.
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.
TRINTOGEN 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 TRINTOGEN or when changing the dose.
The most common adverse reaction was nausea.
| 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
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.
For doses ≥10 mg vortioxetine (as in TRINTOGEN) once daily, the withdrawal rate from the studies was higher in patients aged ≥65 years. For doses of 20 mg vortioxetine (as in TRINTOGEN) once daily, the incidences of nausea and constipation were higher in patients aged ≥65 years (42% and 15%, respectively) than in patients aged <65 years (27% and 4%, respectively) (see section 4.4).
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 TRINTOGEN) was associated with an increase in sexual dysfunction (treatment- emergent sexual dysfunction (TESD)) (see section 5.1).
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 TRINTOGEN.
No information.
No information.
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 "6.04 Adverse Drug Reaction Reporting Form", found online under SAHPRA's publications: https://www.sahpra.org.za/Publications/Index/8
Not applicable.
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