Trintellix

— THERAPEUTIC CATEGORIES —
  • Mood disorders
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Trintellix Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Vortioxetine 5mg, 10mg, 20mg; tabs.

    Pharmacological Class

    Serotonergic agonist and antagonist.

    How Supplied

    Tabs—30, 90, 500

    How Supplied

    Tablets

    • 5mg: pink tab with “5” on one side and “TL” on the other side; supplied as 30-, 90-, and 500-count bottles.

    • 10mg: yellow tab with “10” on one side and “TL” on the other side; supplied as 30-, 90-, and 500-count bottles.

    • 20mg: red tab with “20” on one side and “TL” on the other side; supplied as 30-, 90-, and 500-count bottles.

    Storage

    Store at 77°F (25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature].

    Manufacturer

    Takeda and Lundbeck

    Generic Availability

    NO

    Mechanism of Action

    The mechanism of the antidepressant effect of vortioxetine is thought to be related to its enhancement of serotonergic activity in the CNS through inhibition of the reuptake of serotonin (5-HT). It also has several other activities including 5-HT3 receptor antagonism and 5-HT1A receptor agonism. The contribution of these activities to vortioxetine’s antidepressant effect has not been established.

    Trintellix Indications

    Indications

    Major depressive disorder (MDD).

    Trintellix Dosage and Administration

    Adult

    Initially 10mg once daily; then, increase to 20mg/day, as tolerated. May consider 5mg/day if unable to tolerate. Discontinuing treatment: may reduce to 10mg/day for one week before full discontinuation of 15mg/day or 20mg/day. CYP2D6 poor metabolizers: max 10mg/day. Concomitant strong CYP2D6 inhibitors: reduce vortioxetine dose by ½; increase to original dose when inhibitor is discontinued. Concomitant strong CYP inducers for >14 days: consider increasing vortioxetine dose up to max 3× original dose; reduce to original dose within 14 days when inducer is discontinued.

    Children

    <18yrs: not established.

    Trintellix Contraindications

    Contraindications

    During or within 14 days of MAOIs; do not start an MAOI during or within 21 days of vortioxetine. Concomitant linezolid or IV methylene blue.

    Trintellix Boxed Warnings

    Boxed Warning

    Suicidal thoughts and behaviors.

    Boxed Warning

    Suicidal Thoughts and Behaviors

    • Increased risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies.

    • Monitor all patients for clinical worsening, and for emergence of suicidal thoughts and behaviors.

    Trintellix Warnings/Precautions

    Warnings/Precautions

    Increased risk of suicidal thoughts and behavior in children and young adults; monitor closely for clinical worsening or behavior changes in all patients (esp. during the first few months and at times of dosage changes). Monitor for serotonin syndrome; discontinue if occurs. History of mania/hypomania. Screen for bipolar disorder prior to starting. Risk for bleeding events. Angle-closure glaucoma. Volume depletion. Hyponatremia (esp. elderly). Sexual dysfunction. CYP2D6 poor metabolizers. Avoid abrupt cessation. Elderly. Pregnancy (see full labeling for effects on neonates in 3rd trimester exposure). Nursing mothers.

    Warnings/Precautions

    Suicidal Thoughts and Behaviors in Adolescents and Young Adults

    • Not approved for use in pediatric patients.

    • It is unknown whether the risk of suicidal thoughts/behaviors in adolescents and young adults extends to longer-term use (eg, >4 months).

    • Monitor for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment, and at times of dosage changes.

    • Changes in behavior should be monitored by family members or caregivers.

    • If depression persistently worsens or if emergent suicidal thoughts or behaviors develop, consider changing treatment regimen, including potentially discontinuing 

    Serotonin Syndrome

    • See Interactions.

    • Risk of life-threatening serotonin syndrome: increased risk when Trintellix is used concomitantly with other serotonergic drugs, and drugs that impair metabolism of serotonin.

    • Monitor for emergence of serotonin syndrome.

    • Discontinue immediately if serotonin syndrome occurs and initiate supportive symptomatic treatment.

    Increased Risk of Bleeding 

    • See Interactions.

    • Concomitant use with aspirin, NSAIDs, warfarin, and other anticoagulants increase the risk of bleeding.

    • Advise patients about the increased risk of bleeding when Trintellix is coadministered with NSAIDs, aspirin, or other drugs. 

    • If Trintellix is used with warfarin, monitor coagulation indices when initiating, titrating, or discontinuing Trintellix.

    Activation of Mania/Hypomania

    • Prior to initiation, screen for personal or family history of bipolar disorder, mania, or hypomania.

    • In premarketing clinical studies, symptoms of mania/hypomania were reported in <0.1% of patients treated with Trintellix.

    Discontinuation Syndrome

    • A gradual dosage reduction is recommended when possible. Do not abruptly discontinue Trintellix.

    Angle Closure Glaucoma

    • May trigger an angle closure attack in patients with anatomically narrow angles who do not have a patent iridectomy.

    Hyponatremia

    • There is a greater risk for hyponatremia with serotonergic antidepressant among elderly patients.

    • Institute appropriate medical intervention when discontinuing Trintellix in patients with symptomatic hyponatremia.

    Sexual Dysfunction

    • For male patients: may cause ejaculatory delay or failure, decreased libido, and erectile dysfunction.

    • For female patients: may cause decreased libido and delayed or absent orgasm.

    • Prescribers should inquire patients about sexual function prior to initiation and changes in sexual function during. Discuss potential management strategies to support patients.

    Pregnancy Considerations

    Pregnancy Exposure Registry

    Risk Summary

    • Limited human data on use during pregnancy.

    • Consider the risks of untreated depression when discontinuing or changing treatment with antidepressants during pregnancy and postpartum.

    • Exposure in late pregnancy may result in increased risk for neonatal complications that require prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). 

    • Monitor neonates exposed to Trintellix in the 3rd trimester of pregnancy for PPHN and drug discontinuation syndrome.

    Nursing Mother Considerations

    Risk Summary

    • No information on the presence of vortioxetine in human milk, the effects on the breastfed infant, or the effects on milk production.

    • Consider the developmental and health benefits of breastfeeding, along with the mother's clinical need for Trintellix and any potential adverse effects on the breastfed child from Trintellix or from the underlying maternal condition.

    Pediatric Considerations

    Safety and efficacy have not been established in pediatric patients for the treatment of MDD.

    Geriatric Considerations

    • No dose adjustment is recommended on the basis of age.

    • Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event

    Other Considerations for Specific Populations

    CYP2D6 Poor Metabolizers

    • Recommended to reduce dose in patients known to be poor CYP2D6 metabolizers due to a risk of higher vortioxetine plasma concentrations.

    Trintellix Pharmacokinetics

    Absorption

    The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7–11 hours postdose (Tmax). Steady-state mean Cmax values were 9, 18, and 33 ng/mL (following doses of 5, 10, and 20 mg/day). Absolute bioavailability: 75%. 

    Distribution

    Apparent volume of distribution: ~2600 L, which indicates extensive extravascular distribution. Plasma protein bound: 98%.

    Metabolism

    Oxidation by CYP2D6 (primary enzyme), CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. Poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers.

    Elimination

    Renal (59%), fecal (26%). Half-life: ~66 hours.

    Trintellix Interactions

    Interactions

    See Contraindications. Increased risk of serotonin syndrome with other serotonergic drugs (eg, other SNRIs, SSRIs, triptans, TCAs, fentanyl, lithium, tramadol, tryptophan, meperidine, methadone, buspirone, amphetamines, St. John's Wort) or with drugs that impair serotonin metabolism (eg, MAOIs, linezolid, IV methylene blue). Potentiated by strong CYP2D6 inhibitors (eg, bupropion, fluoxetine, paroxetine, quinidine); see Adult. Antagonized by strong CYP inducers (eg, rifampin, carbamazepine, phenytoin); see Adult. Increased risk of bleeding with concomitant aspirin, NSAIDs, clopidogrel, heparin, warfarin, and others that affect coagulation; monitor. May potentiate other highly protein bound drugs (eg, warfarin). May cause false (+) results in urine enzyme immunoassays for methadone; consider alternative chromatographic methods.

    Trintellix Adverse Reactions

    Adverse Reactions

    Nausea, constipation, diarrhea, vomiting, dizziness, dry mouth; hypersensitivity reactions.

    Trintellix Clinical Trials

    Clinical Trials

    Approval of Trintellix was established in 6 randomized, double-blind, placebo-controlled, fixed-dose studies and 1 maintenance study in adult inpatients and outpatients who met the DSM-IV-TR criteria for MDD.

    Adults (aged 18 years to 75 years)

    • In 5 placebo-controlled studies (Studies 1–5), Trintellix was evaluated in patients 18 to 75 years of age for 6 to 8 weeks. Patients were randomly assigned to receive Trintellix 5mg, 10mg, 15mg, or 20mg or placebo once daily. For Trintellix 15mg/day or 20mg/day, patients were titrated up from 10mg/day after the first week.

    • The primary endpoints were the Hamilton Depression Scale (HAMD-24) total score in Study 2 and the Montgomery-Asberg Depression Rating Scale (MADRS) total score.

    • Results from all studies showed that at least 1 dose group of Trintellix achieved superiority to placebo in improving depressive symptoms for the primary endpoint. 

    • In 2 studies, the 5mg dose in the U.S. did not show effectiveness.

    Elderly Study (aged 64 years to 88 years)

    • In a randomized, double-blind, placebo-controlled, fixed-dose study, the efficacy of Trintellix was evaluated in patients 64 to 88 years of age with MDD. Patients were randomly assigned to receive either Trintellix 5mg or placebo.

    • Results showed that treatment with Trintellix achieved superior to placebo on the Clinical Global Impression of Improvement (CGI-I) scale, which is a clinician’s impression of how much the patient's clinical condition has improved or worsened relative to baseline on a scale of 1 (very much improved) to 7 (very much worse).

    Time Course of Treatment Response

    • In the 6 to 8 week placebo-controlled studies (Study 6), the effects of Trintellix was seen starting at Week 2 on the primary efficacy measure and increased with the full effect not seen until Study Week 4 or later.

    Digit Symbol Substitution Test in Major Depressive Disorder

    • In two 8-week randomized, double-blind, placebo-controlled trials (Studies 7 and 8), the efficacy of Trintellix was evaluated in adults on the Digit Symbol Substitution Test (DSST) during the treatment of acute MDD. 

    • DSST is a neuropsychological test that most specifically measures processing speed, an aspect of cognitive function that may be impaired in MDD. The studies did not include patients whose MDD was in remission and had experienced difficulty concentrating or slow thinking.

    • In Study 7, patients who met the diagnostic criteria for recurrent MDD received Trintellix 10mg, 20mg, or placebo once daily. In Study 8, patients who met the diagnostic criteria for recurrent MDD and reported subjective difficulty concentration or slow thinking received a flexible dose of 10mg or 20mg of Trintellix or placebo once daily.

    • Both studies showed that treatment with Trintellix achieved statistically significantly greater improvement in DSST and depressed mood compared with placebo.

    Non-US Maintenance Study (Study 9)

    • Flexible doses of Trintellix (10mg or 20mg) once daily were administered to 639 patients with MDD during an initial 12-week open-label treatment phase. The dose was fixed during weeks 8 to 12.

    • After open-label treatment, 396 patients who were in remission were randomly assigned to continue the fixed dose of Trintellix or placebo for 24 to 64 weeks.

    • Results showed that treatment with Trintellix achieved a statistically significantly longer time to have recurrence of depressive episodes compared with placebo.

    • Recurrence of depressive episode was defined as a MADRS total score ≥22 or lack of efficacy as judged by the investigator.

    US Maintenance Study (Study 10)

    • A fixed dose of Trintellix 10mg once daily was administered to 1106 patients with MDD during an initial 16-week open-label treatment phase.

    • After open-label treatment, 580 patients who were in remission were randomly assigned 1:1:1:1 to receive Trintellix 5mg, 10mg, 20mg, or placebo once daily for 32 weeks.

    • Results showed that all doses of Trintellix achieved a statistically significantly longer time to have recurrence of depressive episodes compared with placebo.

    • Recurrence of depressive episode was defined as a MADRS total score ≥22 or lack of efficacy as judged by the investigator.

    Trintellix Note

    Notes

    Formerly known as Brintellix.

    Trintellix Patient Counseling

    Patient Counseling

    Suicidal Thoughts and Behaviors

    • Advise to look for the emergence of suicidal ideation and behavior, especially early during treatment and dose adjustments. Report symptoms to healthcare provider.

    Concomitant Medication

    • Inform your healthcare provider of any prescription or OTC medications you are currently taking or plan to take.

    • Do not take Trintellix with MAOI or within 14 days of stopping an MAOI, and allow 21 days after stopping Trintellix before starting an MAOI.

    Serotonin Syndrome

    • Caution about the risk of serotonin syndrome. Report to emergency room if signs or symptoms of serotonin syndrome occur.

    Increased Risk of Bleeding

    • Use of Trintellix with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may increase risk of bleeding.

    • Inform your healthcare provider of any prescription or OTC medications you are currently taking or plan to take.

    Activation of Mania/Hypomania

    • Look for signs of activation.

    Discontinuation of Treatment

    • Do not abruptly stop taking Trintellix.

    Angle Closure Glaucoma

    • May cause mild pupillary dilation which can lead to angle closure glaucoma in susceptible individuals.

    Hyponatremia

    • May be at greater risk of hyponatremia in patients using diuretics, or volume depleted, or are elderly.

    Sexual Dysfunction

    • May cause sexual dysfunction in male and female patients. Discuss any changes and potential management strategies with your healthcare provider.

    Pregnancy

    • Advise pregnant women that Trintellix may cause withdrawal symptoms in the newborn or PPHN.

    Cost Savings Program

    Trintellix Savings & Support

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