enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Decrease vortioxetine dose by 50% when coadministered with strong CYP2D6 inhibitors.rasagilineContraindicated (1)rasagiline increases toxicity of vortioxetine by serotonin levels. Contraindicated.remifentanilSerious - Use Alternative (1)remifentanil, vortioxetine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.remimazolamMonitor Closely (1)remimazolam, vortioxetine. Either increases toxicity of the other by sedation. Modify Therapy/Monitor Closely. Coadministration may result in profound sedation, respiratory depression, coma, and/or death. Continuously monitor vital signs during sedation and recovery period if coadministered. Carefully titrate remimazolam dose if administered with opioid analgesics and/or sedative/hypnotics.reteplaseMonitor Closely (1)reteplase, vortioxetine. Either increases effects of the other by anticoagulation. Use Caution/Monitor.ribociclibMinor (1)ribociclib will increase the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.rifabutinMonitor Closely (2)rifabutin will decrease the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. rifabutin decreases levels of vortioxetine by increasing metabolism. Modify Therapy/Monitor Closely. Consider increasing the vortioxetine dose when coadministered with strong CYP inducers for >14 days; not to exceed 3 times original vortioxetine dose.rifampinMonitor Closely (2)rifampin decreases levels of vortioxetine by increasing metabolism. Modify Therapy/Monitor Closely. Consider increasing the vortioxetine dose when coadministered with strong CYP inducers for >14 days; not to exceed 3 times original vortioxetine dose. rifampin will decrease the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Consider increasing vortioxetine dose when coadministered with a strong CYP inducer for >14 days. Do not exceed 3x the original dose. Reduce vortioxetine dose to original level within 14 days, when inducer is discontinued.rifapentineMonitor Closely (1)rifapentine will decrease the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.ritonavirSerious - Use Alternative (1)ritonavir increases levels of vortioxetine by affecting hepatic enzyme CYP2D6 metabolism. Avoid or Use Alternate Drug. Decrease vortioxetine dose by 50% when coadministered with strong CYP2D6 inhibitors.rivaroxabanMonitor Closely (1)rivaroxaban, vortioxetine. Either increases effects of the other by anticoagulation. Use Caution/Monitor.rizatriptanSerious - Use Alternative (1)rizatriptan, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.rolapitantMonitor Closely (1)rolapitant will increase the level or effect of vortioxetine by affecting hepatic enzyme CYP2D6 metabolism. Use Caution/Monitor. Rolapitant may increase plasma concentrations of CYP2D6 substrates for at least 28 days following rolapitant administration.rucaparibMonitor Closely (1)rucaparib will increase the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.salsalateMonitor Closely (1)salsalate, vortioxetine. Either increases effects of the other by anticoagulation. Use Caution/Monitor.secobarbitalSerious - Use Alternative (1)secobarbital will decrease the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.selegilineContraindicated (1)selegiline increases toxicity of vortioxetine by serotonin levels. Contraindicated.selegiline transdermalContraindicated (1)selegiline transdermal increases toxicity of vortioxetine by serotonin levels. Contraindicated.sertralineSerious - Use Alternative (1)sertraline, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.St John's WortSerious - Use Alternative (1)St John's Wort, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.stiripentolMonitor Closely (1)stiripentol, vortioxetine. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.sufentanilSerious - Use Alternative (1)sufentanil, vortioxetine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.sufentanil SLSerious - Use Alternative (1)sufentanil SL, vortioxetine. Either increases toxicity of the other by serotonin levels. Avoid or Use Alternate Drug.sulindacMonitor Closely (1)sulindac, vortioxetine. Either increases effects of the other by anticoagulation. Use Caution/Monitor.sumatriptanSerious - Use Alternative (1)sumatriptan, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.sumatriptan intranasalSerious - Use Alternative (1)sumatriptan intranasal, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.tazemetostatMonitor Closely (1)tazemetostat will decrease the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.tecovirimatMonitor Closely (1)tecovirimat will decrease the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.tedizolidSerious - Use Alternative (1)tedizolid, vortioxetine. Either increases effects of the other by Mechanism: pharmacodynamic synergism. Avoid or Use Alternate Drug. both increase serotonin levels; increased risk of serotonin syndrome.tenecteplaseMonitor Closely (1)tenecteplase, vortioxetine. Either increases effects of the other by anticoagulation. Use Caution/Monitor.terbinafineMonitor Closely (1)terbinafine will increase the level or effect of vortioxetine by affecting hepatic enzyme CYP2D6 metabolism. Modify Therapy/Monitor Closely. Assess need to reduce dose of CYP2D6-metabolized drug.ticlopidineMonitor Closely (1)ticlopidine increases effects of vortioxetine by anticoagulation. Use Caution/Monitor.tipranavirSerious - Use Alternative (1)tipranavir will increase the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.tirofibanMonitor Closely (1)tirofiban increases effects of vortioxetine by anticoagulation. Use Caution/Monitor.tolmetinMonitor Closely (1)tolmetin, vortioxetine. Either increases effects of the other by anticoagulation. Use Caution/Monitor.tramadolSerious - Use Alternative (1)tramadol, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.tranylcypromineContraindicated (1)tranylcypromine increases toxicity of vortioxetine by serotonin levels. Contraindicated.trazodoneSerious - Use Alternative (1)trazodone increases toxicity of vortioxetine by serotonin levels. Avoid or Use Alternate Drug.trimipramineSerious - Use Alternative (1)trimipramine, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.tucatinibSerious - Use Alternative (1)tucatinib will increase the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.venlafaxineSerious - Use Alternative (1)venlafaxine, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.verapamilSerious - Use Alternative (1)verapamil, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.vilazodoneSerious - Use Alternative (1)vilazodone, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug.vitamin EMonitor Closely (1)vitamin E, vortioxetine. Either increases effects of the other by anticoagulation. Use Caution/Monitor.vorapaxarMonitor Closely (1)vortioxetine, vorapaxar. Either increases effects of the other by anticoagulation. Use Caution/Monitor. Coadministration of anticoagulants, antiplatelets, or other drug affecting coagulation should be monitored periodically due to potential increased risk of bleeding.voxelotorSerious - Use Alternative (1)voxelotor will increase the level or effect of vortioxetine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.warfarinMonitor Closely (1)vortioxetine, warfarin. Either increases effects of the other by pharmacodynamic synergism. Use Caution/Monitor. Serotonin release by platelets plays an important role in hemostasis. SSRIs and SNRIs may increase anticoagulation effect of warfarin. .zolmitriptanSerious - Use Alternative (1)zolmitriptan, vortioxetine. Either increases effects of the other by serotonin levels. Avoid or Use Alternate Drug. >10% Nausea (21-32%) 1-10% Diarrhea (7-10%) Dizziness (6-9%) Dry mouth (6-8%) Constipation (3-6%) Vomiting (3-6%) Flatulence (1-3%) Pruritus (1-3%) Abnormal dreams (<1-3%) Postmarketing Reports Weight gain Acute pancreatitis Angle closure glaucoma Seizure Rash, generalized rash Difficulties in sexual desire, sexual performance, and sexual satisfaction Aggression, agitation, anger, hostility, irritability Black Box Warnings Suicidal thoughts and behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors Not approved for use in pediatric patients Contraindications Hypersensitivity to vortioxetine or any component of formulation MAOI Use of MAOIs (intended to treat psychiatric disorders) or within 21 days of discontinuing with vortioxetine Use of vortioxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders Currently being treated with another MAOI (eg, linezolid, IV methylene blue) Cautions May worsen mania symptoms or activate mania/hypomania in patients with bipolar disorder Risk of mydriasis; may trigger angle closure attack in patients with angle-closure glaucoma with anatomically narrow angles without a patent iridectomy Increases risk of hyponatremia and cognitive impairment especially in the elderly; hyponatremia can occur in association with the syndrome of inappropriate antidiuretic hormone secretion (SIADH); patients taking diuretics or who are otherwise volume-depleted can be at greater risk; consider discontinuation of drug in patients with symptomatic hyponatremia; appropriate medical intervention should be instituted Dosage reduction is recommended in patients known to be poor CYP2D6 metabolizers because these patients have higher vortioxetine plasma concentrations than extensive CYP2D6 metabolizers Suicidal thoughts and behaviors in adolescents and young adults In pooled studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years) taking antidepressants for MDD and other psychiatric illnesses Variations in risk of suicidal thoughts and behaviors among drugs and across the different indications, highest incidence in patients with MDD Unknown if risk extends to longer-term use Closely monitor for behavioral changes, clinical worsening, and suicidal tendencies during initial 1-2 months of therapy and dosage adjustments Counsel family members or caregivers to monitor for changes in behavior and to alert the healthcare provider; consider changing the therapeutic regimen, including possibly discontinuing therapy, in patients whose depression is persistently worse, or who are experiencing emergent of suicidal thoughts and behaviors Serotonin syndrome Serotonin syndrome reported with serotonergic antidepressants (SSRIs, SNRIs, and others), including with vortioxetine, both when taken alone, but especially when coadministered with other serotonergic agents (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort) Symptoms include mental status changes, autonomic instability, neuromuscular symptoms, seizures, and/or gastrointestinal symptoms If symptoms occur, discontinue therapy and initiate supportive treatment If concomitant use with other serotonergic drugs is clinically warranted, advise of potential risks for serotonin syndrome, particularly during treatment initiation and dose increases Discontinuation syndrome Adverse reactions reported upon abrupt discontinuation of treatment at doses of 15-20 mg/day Gradual reduction in dosage is recommended whenever possible Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances, tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures Sexual dysfunction Use may cause symptoms of sexual dysfunction in both male and female patients; inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider Use of SSRIs, may cause symptoms of sexual dysfunction; in male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction In female patients, SSRI/SNRI use may result in decreased libido and delayed or absent orgasm Important for prescribers to inquire about sexual function prior to initiation of therapy and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including underlying psychiatric disorder Discuss potential management strategies to support patients in making informed decisions about treatment Drug interaction overview Substrate of CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 Increase of serotonin syndrome Contraindicated with MAOIs Coadministration with serotonergic drugs increases the risk of serotonin syndrome Monitor; if serotonin syndrome occurs, consider discontinuing vortioxetine Strong CYP2D6 inhibitor Coadministration with strong CYP2D6 inhibitors increases plasma concentrations of vortioxetine Strong CYP inducers Coadministration with strong CYP2D6 inhibitors decreases plasma concentrations of vortioxetine Drugs that interfere coagulation or bleeding Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase risk of abnormal bleeding Exercise caution with concomitant use of vortioxetine with nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents, anticoagulants, or other drugs that affect coagulation Monitor INR when used with warfarin Drugs highly bound to plasma protein Coadministration of vortioxetine with drugs highly bound to plasma protein (eg, warfarin) may increase free concentrations of vortioxetine or other highly bound drugs in plasma Monitor for adverse reactions and reduce dosage of both protein bound drugs as needed Pregnancy Limited human data available on use during pregnancy to inform any drug-associated risks There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy; healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1- 844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/antidepressants/ Animal data Administered to pregnant rats and rabbits during organogenesis at doses ≥15 times and 10x the maximum recommended human dose (MRHD), respectively, resulted in decreased fetal body weight and