Vortioxetine is extensively metabolised in the liver, primarily through oxidation catalysed by CYP2D6 and to a minor extent CYP3A4/5 and CYP2C9 (see Pharmacology: Pharmacokinetics under Actions).
Potential for other medicinal products to affect vortioxetine: Irreversible non-selective MAOIs: Due to the risk of Serotonin Syndrome, vortioxetine is contraindicated in any combination with irreversible non-selective MAOIs. Vortioxetine must not be initiated for at least 14 days after discontinuation of treatment with an irreversible non-selective MAOI. Vortioxetine must be discontinued for at least 14 days before starting treatment with an irreversible non-selective MAOI (see Contraindications).
Reversible, selective MAO-A inhibitor (moclobemide): The combination of vortioxetine with a reversible and selective MAO-A inhibitor, such as moclobemide, is contraindicated (see Contraindications). If the combination proves necessary, the added medicinal product should be given with minimum dosage and under close clinical monitoring for Serotonin Syndrome (see Precautions).
Reversible, non-selective MAOI (linezolid): The combination of vortioxetine with a weak reversible and non-selective MAOI, such as the antibiotic linezolid, is contraindicated (see Contraindications). If the combination proves necessary, the added medicinal product should be given with minimum dosage and under close clinical monitoring for Serotonin Syndrome (see Precautions).
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 with irreversible MAO-B inibitors, such as selegiline or rasagiline should be exercised with caution. Close monitoring for Serotonin Syndrome is necessary if used concomitantly (see Precautions).
Serotonergic medicinal products: Co-administration of medicinal products with serotonergic effect e.g. opioids (including tramadol) and triptans (including sumatriptan) may lead to Serotonin Syndrome (see Precautions).
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 Precautions).
Medicinal products lowering the seizure threshold: 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), mefloquin, bupropion, tramadol] (see Precautions).
ECT (electroconvulsive therapy): There is no clinical experience with concurrent administration of vortioxetine and ECT, therefore caution is advisable.
CYP2D6 inhibitors: 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 150mg 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 the individual patient response, a lower dose of vortioxetine may be considered if strong CYP2D6 inhibitor (e.g. bupropion, quinide, fluoxetine, paroxetine) is added to vortioxetine treatment (see Dosage & Administration).
CYP3A4 inhibitors and CYP2C9, and CYP2C19 inhibitors: When vortioxetine was co-administered following 6 days of ketoconazole 400mg/day (a CYP 3A4/5 and P-glycoprotein inhibitor) or a following 6 days of fluconazole 200mg/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 in healthy subjects.
Interactions in CYP2D6 poor metabolisers: Co-administration of strong inhibitors of CYP3A4 (such as itraconazole, voriconazole, clarithromycin, telitromycin, nefazodone, conivaptan and many of the HIV protease inhibitors) and inhibitors of CYP2C9 (such as fluconazole and amiodarone) to CYP2D6 poor metaboliser (see Pharmacology: Pharmacokinetics under Actions) 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 previously. 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.
Cytochrome P450 inducers: When a single dose of 20mg vortioxetine was co-administered following 10 days of rifampicin 600mg/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 is abroad cytochrome P450 inducer (e.g. rifampicin, carbamazepine, phenytoin) is added to vortioxetine treatment (see Dosage & Administration).
Alcohol: 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 (0.6g/kg) in healthy subjects.
Acetylsalicylic acid: No effect of multiple doses of acetylsalicylic acid 150 mg/day on the multiple-dose pharmacokinetics of vortioxetine was observed in healthy subjects.
Potential for vortioxetine to affect other medicinal products: Anticoagulants and antiplatelet medicinal products: 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 150mg/day was co-administered following multiple doses of vortioxetine administration in healthy subjects. However, as for other serotonergic medicinal products, caution should be exercised when vortioxetine is combined with oral anticoagulants or antiplatelet medicinal products due to a potential increased risk of bleeding attributable to a pharmacodynamic interaction (see Precautions).
Cytochrome P450 substrates: In vitro, vortioxetine did not show any relevant potential for inhibition or induction of cytochrome P450 isoenzymes (see Pharmacology: Pharmacokinetics under Actions).
Following multiple doses of vortioxetine, no inhibitory effect was observed in healthy subjects for the cytochrome P450 isoenzymes CYP2C19 (omeprazole, diazepam), CYP3A4/5 (ethinyl estradiol, midazolam), CYP2B6 (bupropion), CYP2C9 (tolbutamide, S-warfarin), CYP1A2 (caffeine) or CYP2D6 (dextromethorphan).
No pharmacodynamics interactions were observed. No significant impairment, relative to placebo, in cognitive function was observed for vortioxetine following co-administration with a single 10mg 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 30μg/levonorgestrel 150μg).
Lithium, tryptophan: No clinically relevant effect was observed during steady-state lithium exposure following co-administration with multiple dose 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.
Interference with urine drug screens: 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.