Dosage & Administration
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Trintellix Prescribing Information
In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in
| Age Range | Drug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1000 Patients Treated |
|---|---|
Increases Compared to Placebo | |
| <18 years old | 14 additional patients |
| 18 to 24 years old | 5 additional patients |
Decreases Compared to Placebo | |
| 25 to 64 years old | 1 fewer patient |
| ≥65 years old | 6 fewer patients |
It is unknown whether the risk of suicidal thoughts and behaviors in adolescents and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that the use of antidepressants can delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.
Monitor all antidepressant-treated patients for all approved populations for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing TRINTELLIX, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts and behaviors.
The safety and effectiveness of TRINTELLIX have not been established in pediatric patients.
The safety and efficacy of TRINTELLIX were evaluated in two randomized, double-blind, placebo- and active-controlled 8-week studies in pediatric patients with MDD, one in patients 7 to 11 years of age (N=540 randomized) and one in patients 12 to 17 years of age (N=616 randomized). The primary efficacy endpoint for both studies was the change from baseline to week 8 in the Children's Depression Rating Scale-Revised (CDRS-R) total score. The CDRS-R assesses the severity of depression and change in depressive symptoms in children and adolescents with depression. TRINTELLIX was not superior to placebo in either study. Patients from the controlled 8-week studies were eligible to enroll in a 6-month open-label extension study (N=662 treated). Across the three studies, the most commonly observed adverse reactions to TRINTELLIX in pediatric patients 7 to 17 years of age were generally similar to those observed in adults
Antidepressants, such as TRINTELLIX, increase the risk of suicidal thoughts and behaviors in pediatric patients
Administration of vortioxetine to juvenile rats (oral doses of 10, 20, and 40 mg/kg/day twice daily from Postnatal Day 21 to 91) resulted in a neurobehavioral effect at the highest dose of 40 mg/kg twice daily (increased peak auditory startle amplitude) during the treatment period. The effect was not seen at the end of the recovery period. When animals were mated after the 4-week recovery period, viability was decreased in the offspring of mated pairs treated with 40 mg/kg twice daily. The no-observed adverse effect dose was 20 mg/kg twice daily based on both the neurobehavioral and reproductive effects. This dose was associated with plasma vortioxetine exposure (AUC) approximately 2 times that in pediatric patients.
TRINTELLIX is indicated for the treatment of major depressive disorder (MDD) in adults.
- The recommended starting dose is 10 mg administered orally once daily without regard to meals ().
2.1 Recommended DosageThe recommended starting dose is 10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses
[see Clinical Studies (14)]. - The dose should then be increased to 20 mg/day, as tolerated ().
2.1 Recommended DosageThe recommended starting dose is 10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses
[see Clinical Studies (14)]. - Consider 5 mg/day for patients who do not tolerate higher doses ().
2.1 Recommended DosageThe recommended starting dose is 10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses
[see Clinical Studies (14)]. - TRINTELLIX can be discontinued abruptly. However, it is recommended that doses of 15 mg/day or 20 mg/day be reduced to 10 mg/day for one week prior to full discontinuation if possible ().
2.3 Discontinuing TreatmentAlthough TRINTELLIX can be abruptly discontinued, in placebo-controlled trials patients experienced transient adverse reactions such as headache and muscle tension following abrupt discontinuation of TRINTELLIX 15 mg/day or 20 mg/day. It is recommended that the dose be decreased to 10 mg/day for one week before full discontinuation of TRINTELLIX 15 mg/day or 20 mg/day
[see Warnings and Precautions (5.5)and Adverse Reactions (6)]. - The maximum recommended dose is 10 mg/day in known CYP2D6 poor metabolizers ().
2.5 Use of TRINTELLIX in Known CYP2D6 Poor Metabolizers or in Patients Taking Strong CYP2D6 InhibitorsThe maximum recommended dose of TRINTELLIX is 10 mg/day in known CYP2D6 poor metabolizers. Reduce the dose of TRINTELLIX by one-half when patients are receiving a CYP2D6 strong inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) concomitantly. The dose should be increased to the original level when the CYP2D6 inhibitor is discontinued
[see Drug Interactions (7.1), Use in Specific Populations (8.6)].
TRINTELLIX is available as:
- 5 mg: pink, almond shaped biconvex film coated tablet, debossed with "5" on one side and "TL" on the other side
- 10 mg: yellow, almond shaped biconvex film coated tablet, debossed with "10" on one side and "TL" on the other side
- 20 mg: red, almond shaped biconvex film coated tablet, debossed with "20" on one side and "TL" on the other side
Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and withdrawal in the newborn (
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/.
Based on data from published observational studies, exposure to SSRIs or SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage
There are limited human data on TRINTELLIX use during pregnancy to inform any drug-associated risks. However, there are clinical considerations regarding neonates exposed to SSRIs and SNRIs, including TRINTELLIX, during the third trimester of pregnancy
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Exposure to serotonergic antidepressants, including TRINTELLIX, in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). Monitor neonates who were exposed to TRINTELLIX in the third trimester of pregnancy for PPHN and drug discontinuation syndrome
Use of TRINTELLIX in the month before delivery may be associated with an increased risk of postpartum hemorrhage
Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. These findings are based on postmarketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or possibly, a drug discontinuation syndrome. In some cases, the clinical picture was consistent with serotonin syndrome
Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in one to two per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. A study of 831,324 infants born in Sweden in 1997 - 2005 found a PPHN risk ratio of 2.4 (95% CI 1.2-4.3) associated with patient-reported maternal use of SSRIs "in early pregnancy" and a PPHN risk ratio of 3.6 (95% CI 1.2-8.3) associated with a combination of patient-reported maternal use of SSRIs "in early pregnancy" and an antenatal SSRI prescription "in later pregnancy."
In pregnant rats and rabbits, no malformations were seen when vortioxetine was given during the period of organogenesis at oral doses up to 160 and 60 mg/kg/day, respectively. These doses are 77 and 58 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m2basis, in rats and rabbits, respectively. Developmental delay, seen as decreased fetal body weight and delayed ossification, occurred in rats and rabbits at doses equal to and greater than 30 and 10 mg/kg (15 and 10 times the MRHD, respectively) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain). When vortioxetine was administered to pregnant rats at oral doses of 40 and 120 mg/kg (20 and 58 times the MRHD, respectively) throughout pregnancy and lactation, the number of live-born pups was decreased and early postnatal pup mortality was increased. Additionally, pup weights were decreased at birth to weaning at 120 mg/kg and development (specifically eye opening) was slightly delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg (5 times the MRHD).
- Hypersensitivity to vortioxetine or any component of the formulation. Hypersensitivity reactions including anaphylaxis, angioedema, and urticaria have been reported in patients treated with TRINTELLIX [see.]
6.2 Postmarketing ExperienceThe following adverse reactions have been identified during postapproval use of TRINTELLIX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Endocrine disorders —hyperprolactinemiaGastrointestinal System —acute pancreatitisImmune system disorders —hypersensitivity reactions (including anaphylaxis and urticaria)Metabolic disorders —weight gainNervous system disorders —seizure, headachePsychiatric disorders —aggression, agitation, anger, hostility, irritabilityRespiratory, thoracic and mediastinal disorders —anosmia, hyposmiaSkin and subcutaneous tissue disorders —rash, generalized rash, hyperhidrosis - The use of MAOIs intended to treat psychiatric disorders with TRINTELLIX or within 21 days of stopping treatment with TRINTELLIX is contraindicated because of an increased risk of serotonin syndrome. The use of TRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see.,
2.4 Switching a Patient to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric DisordersAt least 14 days must elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with TRINTELLIX to avoid the risk of Serotonin Syndrome
[see Warnings and Precautions (5.2)]. Conversely, at least 21 days must elapse after stopping TRINTELLIX before starting an MAOI intended to treat psychiatric disorders[see Contraindications (4)].]5.2 Serotonin SyndromeSerotonergic antidepressants, including TRINTELLIX, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, meperidine, methadone, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs
[see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone.Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of TRINTELLIX with MAOIs is contraindicated. In addition, do not initiate TRINTELLIX in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking TRINTELLIX, discontinue TRINTELLIX before initiating treatment with the MAOI
[see Contraindications (4), Drug Interactions (7.1)].Monitor all patients taking TRINTELLIX for the emergence of serotonin syndrome. Discontinue treatment with TRINTELLIX and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of TRINTELLIX with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
Starting TRINTELLIX in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome[see.]5.2 Serotonin SyndromeSerotonergic antidepressants, including TRINTELLIX, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, meperidine, methadone, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs
[see Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are used alone.Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of TRINTELLIX with MAOIs is contraindicated. In addition, do not initiate TRINTELLIX in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking TRINTELLIX, discontinue TRINTELLIX before initiating treatment with the MAOI
[see Contraindications (4), Drug Interactions (7.1)].Monitor all patients taking TRINTELLIX for the emergence of serotonin syndrome. Discontinue treatment with TRINTELLIX and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of TRINTELLIX with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.