Mood disorders:

Indications for: TRINTELLIX

Major depressive disorder (MDD).

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.

Adult Dosage:

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 Dosage:

<18yrs: not established.

TRINTELLIX 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.

Boxed Warning:

Suicidal thoughts and behaviors.

TRINTELLIX 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. 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.

TRINTELLIX Classification:

Serotonergic agonist and antagonist.

TRINTELLIX Interactions:

See Contraindications. Increased risk of serotonin syndrome with other serotonergic drugs (eg, other SNRIs, SSRIs, triptans, TCAs, fentanyl, lithium, tramadol, tryptophan, 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 antiplatelets or anticoagulants (eg, NSAIDs, aspirin, clopidogrel, heparin, warfarin); monitor. May potentiate other highly protein bound drugs (eg, warfarin). May cause false (+) results in urine enzyme immunoassays for methadone; consider alternative chromatographic methods.

Adverse Reactions:

Nausea, constipation, diarrhea, vomiting, dizziness, dry mouth.

Note:

Formerly known as Brintellix.

Metabolism:

  • Metabolized 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.

Drug Elimination:

  • Renal (59%), fecal (26%).

  • Half-life: ~66 hours.

Generic Drug Availability:

NO

How Supplied:

Tabs—30, 90, 500