Vortioxetine

Co-administration of strong inhibitors of CYP3A4 (such as itraconazol, 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 has not been investigated specifically, but it is anticipated that it will lead to a more marked increased exposure of vortioxetine in these patients as compared to the moderate effect described above. Depending on individual patient response, a lower dose of vortioxetine 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 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 treatment.

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.

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 administration in healthy subjects. However, caution should be exercised when vortioxetine is combined with oral anticoagulants or antiplatelet medicinal products or medicines used for pain relief (e.g. acetylsalicylic acid (ASA) or NSAIDs), due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction.

Given that subjects with renal or hepatic impairment are vulnerable and given that the data on the use of vortioxetine in these subpopulations are limited, caution should be exercised when treating these patients.

Antidepressants with serotonergic effect can lower the seizure threshold. Caution is advised when concomitantly using other medicinal products capable of lowering the seizure threshold [e.g., antidepressants (tricyclics, SSRIs, SNRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquine, bupropion, tramadol].

No effect on the pharmacokinetics of vortioxetine or ethanol and no significant impairment, relative to placebo, in cognitive function were observed when vortioxetine 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.

The exposure to vortioxetine increased 2.3-fold for area under the curve (AUC) when vortioxetine 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 than when vortioxetine was added to bupropion. Depending on individual patient response, a lower dose of vortioxetine may be considered if strong CYP2D6 inhibitor (e.g. bupropion, quinidine, fluoxetine, paroxetine) is added to vortioxetine treatment.

Co-administration of medicinal products with serotonergic effect e.g. opioids (including tramadol) and triptans (including sumatriptan) may lead to serotonin syndrome.

Fertility studies in male and female rats showed no effect of vortioxetine on fertility, sperm quality or mating performance. Human case reports with medicinal products 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.

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 vortioxetine with these medicinal products should be undertaken with caution.

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

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 old.

Vortioxetine should be used with caution in patients with a history of mania/hypomania and should be discontinued in any patient entering a manic phase.

There is no clinical experience with concurrent administration of vortioxetine and ECT, therefore caution is advisable.

Seizures are a potential risk with antidepressants. Therefore, vortioxetine should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy. Treatment should be discontinued in any patient who develops seizures or for whom there is an increase in seizure frequency.

There have been reports of false positive results in urine enzyme immunoassays for methadone in patients who have taken vortioxetine. Caution should be exercised in the interpretation of positive urine drug screen results, and confirmation by an alternative analytical technique (e.g., chromatographic methods) should be considered.

There are limited data from the use of vortioxetine in pregnant women.

Studies in animals have shown reproductive toxicity.

The following symptoms may occur in the newborn after maternal use of a serotonergic medicinal product 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 treatment, this potential risk cannot be ruled out taking into account the related mechanism of action (increase in serotonin concentrations).

Vortioxetine should only be administered to pregnant women if the expected benefits outweigh the potential risk to the foetus.

Observational data have provided evidence of an increased risk (less than 2-fold) of postpartum haemorrhage following exposure to an SSRI or SNRI within the month prior to birth. Although no studies have investigated an association between vortioxetine treatment and postpartum haemorrhage, there is a potential risk, taking into account the related mechanism of action.

Available data in animals have shown excretion of vortioxetine/vortioxetine metabolites in milk. It is expected that vortioxetine will be excreted into human milk.

A risk to the breastfeeding child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from vortioxetine treatment taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Fertility studies in male and female rats showed no effect of vortioxetine on fertility, sperm quality or mating performance.

Human case reports with medicinal products 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 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.

Summary of the safety profile

The most common adverse reaction was nausea.

Tabulated list of adverse reactions

Adverse reactions are listed below using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). The list is based on information from clinical trials and post-marketing experience.

^* Based on post-marketing cases

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 ≥10 mg vortioxetine once daily, the withdrawal rate from the studies was higher in patients aged ≥65 years.

For doses of 20 mg vortioxetine 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).

Sexual dysfunction

In clinical studies, sexual dysfunction 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 was associated with an increase in sexual dysfunction (TESD). In the post-marketing setting cases of sexual dysfunction have also been reported with doses of vortioxetine below 20 mg.

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 medicinal product 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.

Paediatric population

A total of 304 children aged 7 to 11 years and 308 adolescents aged 12 to 17 years with major depressive disorder (MDD) were treated with vortioxetine in two double-blind, placebo-controlled studies, respectively. In general, the adverse reaction profile of vortioxetine in children and adolescents was similar to that observed inadults except for a higher incidenceof abdominal pain-related events, and a higher incidence of suicidal ideation in adolescents specially, compared to adults.

Two long-term open-label extension studies were performed with vortioxetine doses of 5 to 20 mg/day, and with a treatment duration of 6 months (N=662) and 18 months (N=94), respectively. Overall, the safety and tolerability profile of vortioxetine in the paediatric population after long-term use was comparable to what has been observed after short-term use.

Symptoms upon discontinuation of vortioxetine treatment

In the clinical studies, discontinuation symptoms were systematically evaluated following abrupt cessation of vortioxetine treatment. There was no clinically relevant difference to placebo in the incidence or nature of the discontinuation symptoms after treatment with vortioxetine. Cases describing discontinuation symptoms have been reported in the post-marketing setting and have included symptoms such as dizziness, headache, sensory disturbances (including paraesthesia, electric shock sensations), sleep disturbances (including insomnia), nausea and/or vomiting, anxiety, irritability, agitation, fatigue and tremor. These symptoms may occur within the first week of vortioxetine discontinuation.