brand trintellix 10 mg tablet

Uses

Major Depressive Disorder

Vortioxetine hydrobromide is used for the treatment of major depressive disorder in adults.

The American Psychiatric Association (APA) states that the effectiveness of antidepressants in the treatment of major depressive disorder is generally comparable between and within classes of these medications, including selective serotonin-reuptake inhibitors (SSRIs), serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and other antidepressants (e.g., bupropion, mirtazapine, trazodone). Therefore, the initial selection of an antidepressant can be based mainly on the following factors: patient preference; nature of prior response to medication; safety, tolerability, and anticipated adverse effects; concurrent psychiatric and medical conditions; specific properties of the medication (e.g., half-life, actions on cytochrome P-450 [CYP] isoenzymes, other drug interactions); and cost. For most patients, an SSRI, SNRI, mirtazapine, or bupropion is considered optimal based on these considerations. Clinicians may consult APA's Practice Guidelines for the Treatment of Patients with Major Depressive Disorder (at http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx) for additional information.

The short-term antidepressant efficacy of vortioxetine was established in 6 randomized, double-blind, placebo-controlled, fixed-dose studies of 6-8 weeks' duration in adult inpatients and outpatients who met DSM-IV-TR criteria for major depressive disorder, including one study in geriatric patients. In 5 of these studies, adult patients 18-75 years of age were randomized to receive either vortioxetine 5, 10, 15, or 20 mg or placebo given once daily. The primary efficacy measure was the Hamilton Depression Scale (HAMD-24) total score in one study (study 2) and the Montgomery-Asberg Depression Rating Scale (MADRS) total score in the other studies. In each of these studies, at least one dosage group of vortioxetine was found to be more effective than placebo in improving depressive symptoms as measured by the mean change from baseline to end point visit on the HAMD-24 or MADRS total score. The remaining study (study 6) demonstrated the antidepressant efficacy of vortioxetine (5 mg once daily) in geriatric patients 64-88 years of age with recurrent major depressive disorder (with at least one previous episode before the age of 60 years) and without concomitant cognitive impairment.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.) An antidepressant effect was generally observed in vortioxetine-treated patients beginning at week 2 and increased during subsequent weeks; the full antidepressant effect generally was not seen until week 4 or later. No age-, gender-, or race-related differences in response to vortioxetine were noted in the adult studies.

Two randomized, double-blind, placebo-controlled studies of vortioxetine 5 mg once daily conducted in the US failed to demonstrate effectiveness of this dosage in the treatment of major depressive disorder in adults.

In a long-term, multicenter, non-US maintenance study, 639 adult inpatients or outpatients who met DSM-IV-TR criteria for major depressive disorder initially received open-label vortioxetine therapy (given in a flexible dosage of 5 or 10 mg once daily during the first 8 weeks of the initial 12-week treatment phase; dosage was fixed between weeks 8-12). Patients in remission at weeks 10 and 12 were then randomized either to continue fixed-dosage vortioxetine therapy at the final dosage they had responded to (approximately 75% were receiving 10 mg daily) or to receive placebo for 24-64 weeks. Patients receiving vortioxetine experienced a longer time to recurrence of depressive episodes compared with patients receiving placebo. In addition, fewer patients receiving vortioxetine (13%) experienced a relapse compared with those receiving placebo (26%). In 2 additional long-term (52-week), multicenter, open-label, extension studies, vortioxetine (2.5-10 mg once daily) was found to be effective and well tolerated in adults with major depressive disorder. Laboratory, vital sign, and ECG findings in these 2 studies did not reveal any clinically important safety issues with long-term vortioxetine therapy.

Dosage and Administration

Administration

Vortioxetine hydrobromide is commercially available as immediate-release tablets, which are administered orally once daily without regard to meals, at approximately the same time each day.

Patients receiving vortioxetine should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

The manufacturer states that at least 2 weeks must elapse between discontinuance of a monoamine oxidase (MAO) inhibitor intended to treat psychiatric disorders and initiation of vortioxetine therapy and at least 3 weeks must elapse between discontinuance of vortioxetine and initiation of MAO inhibitor therapy intended to treat psychiatric disorders. (See Contraindications, Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions, and Drug Interactions: Monoamine Oxidase Inhibitors.)

Prescribing and Dispensing Precautions

Prescribing and dispensing errors have been reported because of similarities in the spelling and pronunciation of Brintellix (the former trade name for vortioxetine hydrobromide) and Brilinta (the trade name for ticagrelor, a platelet-aggregation inhibitor). To avoid such errors, the manufacturer of Brintellix changed the trade name for vortioxetine hydrobromide from Brintellix to Trintellix, which became commercially available in June 2016. (See Prescribing and Dispensing Precautions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Dosage

Dosage of vortioxetine hydrobromide is expressed in terms of vortioxetine.

Major Depressive Disorder

For the management of major depressive disorder in adults, the recommended initial dosage of vortioxetine is 10 mg orally once daily, which should then be increased to 20 mg once daily, as tolerated, because higher dosages demonstrated better efficacy in clinical trials conducted in the US. In the main clinical trials, dosage increases were made after the first week. The manufacturer states that the efficacy and safety of dosages greater than 20 mg daily have not been evaluated in controlled clinical trials. A dosage decrease to 5 mg daily should be considered in patients who do not tolerate higher dosages of the drug.

In known poor metabolizers of the cytochrome P-450 (CYP) isoenzyme 2D6, the maximum recommended dosage of vortioxetine is 10 mg once daily.

The dosage of vortioxetine should be reduced by 50% when used concurrently with potent CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine, quinidine). The dosage should then be increased back to the original dosage when the CYP2D6 inhibitor is discontinued.(See Drug Interactions.)

During concomitant use with potent CYP inducers (e.g., carbamazepine, phenytoin, rifampin) for longer than 14 days, an increase in the vortioxetine dosage should be considered. However, the manufacturer recommends that the maximum dosage not exceed 3 times the original dosage. The dosage should then be reduced back to the original dosage when the CYP inducer is discontinued.(See Drug Interactions.)

It is generally agreed that acute depressive episodes require several months or longer of sustained antidepressant therapy in responding patients. In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with chronic and recurrent major depressive disorder).

Discontinuance of Therapy

Although vortioxetine can be abruptly discontinued, patients in placebo-controlled trials experienced transient adverse reactions (including headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, runny nose) in the first week following abrupt discontinuance of vortioxetine 15 or 20 mg daily. To avoid such possible adverse reactions, the manufacturer recommends that the dosage be decreased to 10 mg daily for one week before full discontinuance of vortioxetine if given at a dosage of 15 or 20 mg daily, if possible.

Special Populations

Dosage adjustment is not necessary in patients with renal impairment (ranging from mild renal impairment to end-stage renal disease).(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

In patients with mild or moderate hepatic impairment, dosage adjustment is not necessary. Because vortioxetine has not been studied in patients with severe hepatic impairment, the manufacturer states that use in such patients is not recommended.

No dosage adjustment is necessary in geriatric patients. In addition, dosage adjustment is not recommended based on gender, race, or ethnicity.

Cautions

Contraindications

Known hypersensitivity to vortioxetine or any ingredients in the formulation. Angioedema has been reported in vortioxetine-treated patients.

Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase (MAO) inhibitor intended to treat psychiatric disorders. Use of an MAO inhibitor intended to treat psychiatric disorders within 3 weeks of vortioxetine discontinuance. (See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Drug Interactions: Monoamine Oxidase Inhibitors.)

Initiation of vortioxetine therapy in patients receiving MAO inhibitors such as linezolid or IV methylene blue. (See Drug Interactions: Linezolid and also see Drug Interactions: Methylene Blue.)

Warnings/Precautions

Warnings

Worsening of Depression and Suicidality Risk

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants. This risk may persist until clinically important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

Other Warnings and Precautions

Serotonin Syndrome

Potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants, including vortioxetine, when used alone, but particularly with concurrent use of other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [''triptans''], tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort [Hypericum perforatum]) and with drugs that impair the metabolism of serotonin (particularly MAO inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue). Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea). Patients receiving vortioxetine should be monitored for the development of serotonin syndrome.

Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated. Use of an MAO inhibitor intended to treat psychiatric disorders within 3 weeks of vortioxetine discontinuance also is contraindicated. (See Contraindications and also see Drug Interactions: Monoamine Oxidase Inhibitors.) Vortioxetine also should not be initiated in patients who are being treated with other MAO inhibitors such as linezolid or IV methylene blue. (See Drug Interactions: Linezolid and also see Drug Interactions: Methylene Blue.)

If concurrent therapy with vortioxetine and other serotonergic drugs is clinically warranted, the patient should be made aware of the potential increased risk for serotonin syndrome, particularly during initiation of therapy or when dosage is increased.(See Drug Interactions.)

If manifestations of serotonin syndrome occur, treatment with vortioxetine and any concurrently administered serotonergic agents should be immediately discontinued and supportive and symptomatic treatment initiated.

For further information on serotonin syndrome, including manifestations and treatment,

Abnormal Bleeding

Serotonergic antidepressants, including vortioxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiologic studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. The manufacturer recommends that patients be advised of the increased risk of bleeding associated with concomitant use of vortioxetine and aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation or bleeding.(See Drug Interactions: Drugs Affecting Hemostasis.)

Activation of Mania/Hypomania

Symptoms of mania and hypomania have been reported in less than 0.1% of patients receiving vortioxetine in clinical studies. Activation of mania and hypomania also have been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. Vortioxetine should therefore be used with caution in patients with a personal or family history of bipolar disorder, mania, or hypomania.

Angle-closure Glaucoma

The pupillary dilation (mydriasis) that occurs following the use of many antidepressant agents, including vortioxetine, may trigger an acute attack of angle-closure glaucoma (narrow-angle glaucoma) in patients with anatomically narrow angles who do not have a patent iridectomy.(See Advice to Patients.)

Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion

Treatment with serotonergic drugs, including vortioxetine, may result in hyponatremia. In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case of hyponatremia with a serum sodium concentration lower than 110 mmol/L has been reported with vortioxetine in a premarketing study. Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia with serotonergic antidepressants. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death. Vortioxetine should be discontinued and appropriate medical intervention should be instituted in patients with symptomatic hyponatremia.

Prescribing and Dispensing Precautions

Because of similarities in the spelling and pronunciation of Brintellix (the former trade name for vortioxetine hydrobromide) and Brilinta (the trade name for ticagrelor, a platelet-aggregation inhibitor), prescribing and dispensing errors have been reported to FDA for these drugs. As of June 2015, the FDA had received 50 medication error reports describing trade name confusion with Brintellix and Brilinta. In most cases, Brintellix was mistaken for Brilinta. The wrong drug was actually dispensed in 12 of the reported cases of name confusion; however, none of the reports indicated that a patient ingested the wrong drug. To avoid future prescribing and dispensing errors, FDA approved a change in the trade name for vortioxetine in May 2016; the manufacturer of Brintellix changed the trade name for vortioxetine hydrobromide to Trintellix; the drug became commercially available under this trade name in June 2016. To reduce the risk of medication errors (e.g., during the transition period to the new name), FDA recommends that clinicians include both the trade (brand) and generic (nonproprietary) names of the drug and the indication for use, as well as the correct dosage, and directions for use in each prescription. In addition, patients should be advised to check their prescriptions to ensure that the correct drug was dispensed and to carefully read the medication guide provided with their prescriptions.

Specific Populations

Pregnancy

Category C.

Some neonates exposed to SSRIs or SNRIs late in the third trimester of pregnancy have developed complications, which have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special-care nurseries. Such complications may arise immediately upon delivery and usually last several days or up to 2-4 weeks. Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features appear to be consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug withdrawal syndrome. In some cases, the clinical picture was consistent with serotonin syndrome (see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions).

For additional information on the management of depression in women prior to conception and during pregnancy, including treatment algorithms, clinicians may consult the joint American Psychiatric Association and American College of Obstetricians and Gynecologists guidelines (at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103063/pdf/nihms293836.pdf).

Lactation

Vortioxetine is distributed into milk in rats. It is not known whether the drug is distributed into human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Clinical studies of vortioxetine in pediatric patients have not been conducted; therefore, the safety and effectiveness of the drug in pediatric patients have not been established.

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants). However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or ideation. No suicides occurred in these pediatric trials. These findings should be carefully considered when assessing potential benefits and risks of vortioxetine in a child or adolescent for any clinical use.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Geriatric Use

In clinical trials with vortioxetine, 11% of the patients were 65 years of age or older, including in a placebo-controlled study conducted specifically in geriatric patients. No overall differences in safety or effectiveness were observed between geriatric and younger adults in these studies; other reported clinical experience has not identified any differences in response to the drug between geriatric and younger adults.

No dosage adjustment is necessary in geriatric patients. In a single-dose pharmacokinetic study, the pharmacokinetics of vortioxetine generally were similar between geriatric individuals older than 65 years of age and younger individuals (24-45 years of age).

Serotonergic antidepressants, including vortioxetine, have been associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect.(See Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Hepatic Impairment

Dosage adjustment of vortioxetine is not necessary in patients with mild or moderate hepatic impairment. However, vortioxetine has not been studied in patients with severe hepatic impairment and use in such patients is not recommended.

Renal Impairment

The presence of mild, moderate, or severe renal impairment or end-stage renal disease does not affect the apparent clearance or the plasma protein binding of vortioxetine. Dosage adjustment of vortioxetine is not necessary in patients with renal impairment (ranging from mild renal impairment to end-stage renal disease).

Only a small fraction of a single, 10-mg dose of vortioxetine was removed by dialysis; area under the concentration-time curve and peak plasma concentrations were 13 and 27% lower postdialysis, respectively.

Common Adverse Effects

Adverse effects reported in at least 5% of patients with major depressive disorder receiving vortioxetine and at an incidence of at least twice that reported with placebo in controlled clinical studies include nausea, constipation, and vomiting. Nausea was the most common adverse effect in these studies and it occurred most often during the first week of treatment; the incidence of nausea was dose related and higher in females than in males.

Drug Interactions

Vortioxetine is metabolized principally by cytochrome P-450 (CYP) isoenzyme 2D6 with lesser contributions from CYP3A4/5, 2C19, 2C9, 2A6, 2C8, and 2B6. In vitro and in vivo studies have demonstrated that vortioxetine and its metabolites are unlikely to inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5. In an in vitro study, vortioxetine did not induce CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 3A4/5.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2D6 Inhibitors

The dosage of vortioxetine should be reduced by 50% when used concurrently with potent CYP2D6 inhibitors (e.g., bupropion, fluoxetine, paroxetine, quinidine). The dosage should be increased back to the original dosage when the CYP2D6 inhibitor is discontinued.

Potent CYP Inducers

When administered with a potent CYP inducer (e.g., carbamazepine, phenytoin, rifampin) for longer than 14 days, increasing the dosage of vortioxetine should be considered. The manufacturer recommends that the maximum dosage of vortioxetine not exceed 3 times the original dosage. Following discontinuance of the potent CYP inducer, the original vortioxetine dosage should be resumed within 14 days.

Drugs Metabolized by Hepatic Microsomal Enzymes

The manufacturer states that clinically important pharmacokinetic interactions are unlikely and that dosage adjustment of the concurrently administered drug is not necessary when vortioxetine is used concurrently with substrates of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinide), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), or CYP3A4/5 (e.g., budesonide). Clinically important pharmacokinetic drug interactions also are unlikely during concurrent administration of substrates of CYP2E1.

In an in vivo study, no clinically important pharmacokinetic interaction was observed during concomitant administration of vortioxetine and caffeine (a CYP1A2 substrate), tolbutamide (a CYP2C9 substrate), or midazolam (a CYP3A4 substrate).

No clinically important pharmacokinetic interaction has been observed during concomitant administration of vortioxetine and warfarin (a CYP2C9 substrate) or diazepam (a CYP2C19 substrate).

Chronic administration of vortioxetine is unlikely to induce the metabolism of drugs metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 3A4/5.

Drugs Affecting or Affected by P-glycoprotein Transport

Vortioxetine is a poor P-glycoprotein (P-gp) substrate and inhibitor. The manufacturer states that no dosage adjustment is necessary when a P-gp substrate is concurrently administered with vortioxetine.

Monoamine Oxidase Inhibitors

Potentially serious, sometimes fatal adverse reactions may occur in patients who are receiving or have recently received a monoamine oxidase (MAO) inhibitor and then initiate therapy with serotonergic antidepressants or in those who received SSRI or SNRI therapy shortly before initiation of an MAO inhibitor. Concomitant use of MAO inhibitors intended to treat psychiatric disorders with vortioxetine is contraindicated. In addition, at least 2 weeks should elapse between discontinuance of an MAO inhibitor intended to treat psychiatric disorders and initiation of vortioxetine and at least 3 weeks should elapse between discontinuance of vortioxetine and initiation of an MAO inhibitor intended to treat psychiatric disorders. (See Contraindications and also see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Linezolid

Linezolid, an anti-infective agent that is also a reversible MAO inhibitor, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs and SNRIs. Because of this potential risk, linezolid generally should not be used in patients receiving vortioxetine. However, the manufacturer and the US Food and Drug Administration (FDA) state that certain life-threatening or urgent situations necessitate immediate linezolid treatment in a patient receiving a serotonergic drug such as vortioxetine. In such emergency situations, the availability of alternative anti-infectives should be considered and the benefits of linezolid should be weighed against the risk of serotonin syndrome. If linezolid is indicated in such emergency situations, vortioxetine must be immediately discontinued and the patient monitored for symptoms of CNS toxicity for 3 weeks or until 24 hours after the last linezolid dose, whichever comes first. Treatment with vortioxetine may be resumed 24 hours after the last linezolid dose.

If nonemergency use of linezolid is being planned for a patient receiving vortioxetine, vortioxetine should be withheld for at least 2 weeks prior to initiating linezolid.

Treatment with vortioxetine should not be initiated in a patient receiving linezolid. In patients who require more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. Vortioxetine may be started 24 hours after the last linezolid dose. (See Contraindications and also see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Methylene Blue

Methylene blue, a potent and reversible inhibitor of MAO-A, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs and SNRIs. Most of these cases occurred when methylene blue was used as a diagnostic (visualizing) dye (1-8 mg/kg IV) during parathyroid surgery; it is unclear whether there is a risk of serotonin syndrome when methylene blue is administered by other routes or in lower IV doses in patients receiving serotonergic drugs. Because of this potential risk, methylene blue generally should not be used in patients receiving vortioxetine. However, the manufacturer and the FDA state that certain life-threatening or urgent situations may necessitate immediate IV methylene blue treatment in a patient receiving a serotonergic drug such as vortioxetine. In such emergency situations, the availability of alternative interventions should be considered and the benefits of methylene blue should be weighed against the risk of serotonin syndrome. If methylene blue is indicated in such emergency situations, vortioxetine must be immediately discontinued and the patient monitored for symptoms of CNS toxicity for 3 weeks or until 24 hours after the last methylene blue dose, whichever comes first. Treatment with vortioxetine may be resumed 24 hours after the last methylene blue dose.

If nonemergency use of methylene blue is being planned for a patient receiving vortioxetine, vortioxetine should be withheld for at least 2 weeks prior to initiating methylene blue treatment.

Treatment with vortioxetine should not be initiated in a patient receiving IV methylene blue. In patients who require more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered. Vortioxetine may be started 24 hours after the last IV methylene blue dose. (See Contraindications and also see Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

The manufacturer of vortioxetine states that the risk of administering methylene blue by non-IV routes (e.g., oral tablets, local injection) or in IV doses much lower than 1 mg/kg in patients receiving vortioxetine is unclear. Clinicians should be aware of the possibility of the emergent symptoms of serotonin syndrome with concomitant use.

Serotonergic Drugs

Concomitant use of vortioxetine and other serotonergic drugs is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and other serotonergic drugs is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with vortioxetine and any concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Concomitant use of vortioxetine and a selective serotonin-reuptake inhibitor (SSRI) or selective serotonin- and norepinephrine-reuptake inhibitor (SNRI) is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and an SSRI or SNRI is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with vortioxetine and the concurrently administered SSRI or SNRI should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Duloxetine

The manufacturer states that dosage adjustment of duloxetine (a CYP1A2 substrate) is not necessary when used concomitantly with vortioxetine.

Fluoxetine and Paroxetine

The dosage of vortioxetine should be reduced by 50% when used concurrently with fluoxetine or paroxetine, which are both potent CYP2D6 inhibitors. The dosage should be increased back to the original dosage when fluoxetine or paroxetine is discontinued.(See Potent CYP2D6 Inhibitors under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Venlafaxine

The manufacturer states that dosage adjustment of venlafaxine (a CYP2D6 substrate) is not necessary when used concomitantly with vortioxetine.

Tricyclic Antidepressants

Concomitant use of vortioxetine and a tricyclic antidepressant is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and a tricyclic antidepressant is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with vortioxetine, the tricyclic antidepressant, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

5-HT1 Receptor Agonists (''Triptans'')

Concomitant use of vortioxetine and a triptan is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and triptans is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with vortioxetine, the triptan, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Tryptophan

Concomitant use of vortioxetine and tryptophan is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and tryptophan is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with vortioxetine, tryptophan, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Buspirone

Concomitant use of vortioxetine and buspirone is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and buspirone is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with vortioxetine, buspirone, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Fentanyl

Concomitant use of vortioxetine and fentanyl is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and fentanyl is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with vortioxetine, fentanyl, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

St. John's Wort

Concomitant use of vortioxetine and St. John's wort (Hypericum perforatum) is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and St. John's wort is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with vortioxetine, St. John's wort, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Tramadol

Concomitant use of vortioxetine and tramadol is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and tramadol is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with vortioxetine, tramadol, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Drugs Affecting Hemostasis

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs were administered concurrently with warfarin.

Following concurrent administration of stable doses of warfarin (1-10 mg daily) with multiple daily doses of vortioxetine (10 mg daily), no clinically important effects were observed on international normalized ratio (INR), prothrombin values, or warfarin pharmacokinetics (protein-bound and free drug) for both R- and S-warfarin. The manufacturer of vortioxetine states that dosage adjustment of warfarin is not necessary when these drugs are given in combination.

The risk of bleeding may be increased if vortioxetine is used concurrently with aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs).

Concurrent administration of aspirin (150 mg daily) with multiple daily doses of vortioxetine did not have a clinically important inhibitory effect on platelet aggregation or the pharmacokinetics of aspirin and salicylic acid. The manufacturer states that dosage adjustment of aspirin is not necessary when these drugs are given in combination.

Patients receiving other drugs that interfere with hemostasis should be carefully monitored when vortioxetine is initiated or discontinued.

Drugs Highly Bound to Plasma Protein

Vortioxetine is highly bound to plasma proteins and concurrent administration of vortioxetine in patients receiving another drug that is highly protein bound potentially may result in increased free concentrations of the other drug.(See Drug Interactions: Drugs Affecting Hemostasis.)

Alcohol

In a clinical study, vortioxetine (single 20- or 40-mg dose) did not increase impairment of mental and motor skills caused by alcohol. However, the manufacturer recommends avoiding concomitant alcohol consumption during vortioxetine therapy.

Budesonide

The manufacturer of vortioxetine states that dosage adjustment of budesonide (a CYP3A4/5 substrate) is not necessary during concurrent administration of vortioxetine.

Bupropion

Concurrent administration of vortioxetine (10 mg once daily) and bupropion (75 or 150 mg twice daily), a potent CYP2D6 inhibitor and CYP2B6 substrate, in healthy individuals increased peak plasma concentrations of bupropion by 18%, and increased vortioxetine peak plasma concentrations and area under the concentration-time curve (AUC) by 114 and 128%, respectively. Increased adverse effects also were observed when vortioxetine and bupropion were given in combination, probably as a result, at least in part, of increased vortioxetine exposure.

Dosage adjustment of bupropion is not necessary when concomitantly administered with vortioxetine. However, the dosage of vortioxetine should be reduced by 50% when used concurrently with bupropion. The dosage of vortioxetine should be increased back to the original dosage when bupropion is discontinued.(See Potent CYP2D6 Inhibitors under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Caffeine

Multiple doses of vortioxetine did not have a clinically important effect on the pharmacokinetics of caffeine (a CYP1A2 substrate) in healthy individuals.

Carbamazepine

When vortioxetine is administered concurrently with carbamazepine (a potent CYP inducer) for longer than 14 days, increasing the dosage of vortioxetine should be considered. The manufacturer recommends that the maximum dosage of vortioxetine not exceed 3 times the original dosage. Following discontinuance of carbamazepine, the original vortioxetine dosage should be resumed within 14 days.

Diazepam

Multiple daily doses of vortioxetine did not affect the pharmacokinetics or pharmacodynamics (i.e., composite cognitive score) of diazepam (a CYP2C19 substrate). The manufacturer of vortioxetine states that dosage adjustment of diazepam is not necessary during concurrent administration of vortioxetine.

Diuretics

Concomitant use of vortioxetine and diuretics may increase the risk of hyponatremia.(See Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Fluconazole

Administration of a single dose of vortioxetine (10 mg) to healthy individuals receiving fluconazole (200 mg once daily) increased peak plasma concentrations and AUC of vortioxetine by 15 and 46%, respectively; these increases were not considered clinically important. Dosage adjustment of fluconazole therefore is not necessary when administered concomitantly with vortioxetine.

Ketoconazole

Administration of a single dose of vortioxetine (10 mg) to healthy individuals receiving ketoconazole (400 mg once daily) increased peak plasma concentration and AUC of vortioxetine by 26 and 30%, respectively; these increases were not considered clinically important. Dosage adjustment of ketoconazole therefore is not necessary when administered concomitantly with vortioxetine.

Lithium

Administration of multiple daily doses of vortioxetine with lithium (at steady state) did not have a clinically important effect on lithium exposure. The manufacturer of vortioxetine states that dosage adjustment of lithium is not necessary when these drugs are given in combination.

Concomitant use of vortioxetine and lithium is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and lithium is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases (see Advice to Patients). If serotonin syndrome manifestations occur, treatment with vortioxetine, lithium, and any other concurrently administered serotonergic agents should be discontinued immediately and supportive and symptomatic treatment should be initiated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Midazolam

Multiple doses of vortioxetine did not have a clinically important effect on the pharmacokinetics of midazolam (a CYP3A4 substrate) in healthy individuals.

Omeprazole

Administration of a single 40-mg dose of omeprazole (a CYP2C19 inhibitor and substrate) to healthy individuals receiving vortioxetine (10 mg once daily) did not have a clinically important effect on the pharmacokinetics of either drug.

Oral Contraceptives

Vortioxetine (10 mg once daily) did not have a clinically important effect on the pharmacokinetics of concurrently administered ethinyl estradiol (0.03 mg) and levonorgestrel (0.15 mg).

Phenytoin

When vortioxetine is administered concurrently with phenytoin (a potent CYP inducer) for longer than 14 days, increasing the dosage of vortioxetine should be considered. The manufacturer of vortioxetine recommends that the maximum dosage of vortioxetine not exceed 3 times the original dosage. Following discontinuance of phenytoin, the original vortioxetine dosage should be resumed within 14 days.

Quinidine

The dosage of vortioxetine should be reduced by 50% when used concurrently with quinidine, a potent CYP2D6 inhibitor. The dosage should be increased back to the original dosage when quinidine is discontinued.(See Potent CYP2D6 Inhibitors under Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Repaglinide

The manufacturer of vortioxetine states that dosage adjustment of repaglinide (a CYP2C8 substrate) is not necessary during concurrent administration of vortioxetine.

Rifampin

Administration of a single dose of vortioxetine (20 mg) to healthy individuals receiving rifampin (a potent CYP inducer; 600 mg once daily for 10 days) decreased peak plasma concentrations and AUC of vortioxetine by 51 and 72-77%, respectively. When vortioxetine is administered concurrently with rifampin for longer than 14 days, increasing the dosage of vortioxetine should be considered. The manufacturer of vortioxetine recommends that the maximum dosage of vortioxetine not exceed 3 times the original dosage. Following discontinuance of rifampin, the original vortioxetine dosage should be resumed within 14 days.

Tolbutamide

Multiple doses of vortioxetine did not have a clinically important effect on the pharmacokinetics of tolbutamide (a CYP2C9 substrate) in healthy individuals.