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Dosage & administration

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Trintellix prescribing information

Boxed Warning

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
[see
5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

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

Table 1
.

Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in PediatricTRINTELLIX is not approved for use in pediatric patients.and Adult Patients
Age RangeDrug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1000 Patients Treated
Increases Compared to Placebo
<18 years old14 additional patients
18 to 24 years old5 additional patients
Decreases Compared to Placebo
25 to 64 years old1 fewer patient
≥65 years old6 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.

]
. TRINTELLIX is not approved for use in pediatric patients
[see
8.4 Pediatric Use

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

.

Juvenile Animal Toxicity Data

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.

]
.

Indications & Usage

TRINTELLIX is indicated for the treatment of major depressive disorder (MDD) in adults.

Dosage & Administration
  • The recommended starting dose is 10 mg administered orally once daily without regard to meals (
    2.1 Recommended Dosage

    The 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

    .

    ).
  • The dose should then be increased to 20 mg/day, as tolerated (
    2.1 Recommended Dosage

    The 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

    .

    ).
  • Consider 5 mg/day for patients who do not tolerate higher doses (
    2.1 Recommended Dosage

    The 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

    .

    ).
  • 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 Treatment

    Although 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

    .

    ).
  • 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 Inhibitors

    The 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

    .

    ).
Dosage Forms & Strengths

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 & Lactation

Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and withdrawal in the newborn (

8.1 Pregnancy

Pregnancy Exposure Registry

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/.

Risk Summary

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

. Vortioxetine administered to pregnant rats and rabbits during the period of organogenesis at doses ≥15 times and 10 times the maximum recommended human dose (MRHD), respectively, resulted in decreased fetal body weight and delayed ossification. No malformations were seen at doses up to 77 times and 58 times the MRHD, respectively. Vortioxetine administered to pregnant rats during gestation and lactation at oral doses ≥20 times the MRHD resulted in a decrease in the number of live-born pups and an increase in early postnatal pup mortality. Decreased pup weight at birth to weaning occurred at 58 times the MRHD and delayed physical development occurred at ≥20 times the MRHD. These effects were not seen at 5 times the MRHD
[seeData]
. Advise a pregnant woman of the potential risk to a fetus.

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.

Clinical Considerations

Disease-associated Maternal and/or Embryo/Fetal Risk

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.

Fetal/Neonatal Adverse Reactions

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

[seeData]
.

Maternal Adverse Reactions

Use of TRINTELLIX in the month before delivery may be associated with an increased risk of postpartum hemorrhage

Data

Human Data

Third Trimester Exposure

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."

Animal Data

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).

).

Contraindications
  • 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 Experience

    The 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 —
    hyperprolactinemia

    Gastrointestinal System —
    acute pancreatitis

    Immune system disorders —
    hypersensitivity reactions (including anaphylaxis and urticaria)

    Metabolic disorders —
    weight gain

    Nervous system disorders —
    seizure, headache

    Psychiatric disorders —
    aggression, agitation, anger, hostility, irritability

    Respiratory, thoracic and mediastinal disorders —
    anosmia, hyposmia

    Skin 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 Disorders

    At 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

    . Conversely, at least 21 days must elapse after stopping TRINTELLIX before starting an MAOI intended to treat psychiatric disorders.

    ,
    5.2 Serotonin Syndrome

    Serotonergic 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

    . 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

    .

    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 Syndrome

    Serotonergic 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

    . 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

    .

    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.

    ]
    .
Warnings & Precautions
  • Serotonin Syndrome
    : Increased risk when coadministered with other serotonergic agents, but also when taken alone. If it occurs, discontinue TRINTELLIX and serotonergic agents and initiate supportive measures (
    5.2 Serotonin Syndrome

    Serotonergic 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

    . 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

    .

    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.

    ).
  • Increased Risk of Bleeding
    : Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, or other drugs that affect coagulation may increase risk (
    5.3 Increased Risk of Bleeding

    The use of drugs that interfere with serotonin reuptake inhibition, including TRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the 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

    . Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

    Inform patients about the increased risk of bleeding when TRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing TRINTELLIX

    .

    ).
  • Activation of Mania/Hypomania
    : Screen patients for bipolar disorder (
    5.4 Activation of Mania/Hypomania

    In patients with bipolar disorder, treating a depressive episode with TRINTELLIX or another antidepressant may precipitate a mixed/manic episode. Symptoms of mania/hypomania were reported in <0.1% of patients treated with TRINTELLIX in premarketing clinical studies. Prior to initiating treatment with TRINTELLIX, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

    ).
  • Angle Closure Glaucoma:
    Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants (
    5.6 Angle Closure Glaucoma

    The pupillary dilation that occurs following use of many antidepressant drugs, including TRINTELLIX, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

    ).
  • Hyponatremia
    : Can occur in association with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (
    5.7 Hyponatremia

    Hyponatremia has occurred as a result of treatment with serotonergic drugs, including TRINTELLIX. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with serum sodium lower than 110 mmol/L was reported in a subject treated with TRINTELLIX in a premarketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of TRINTELLIX in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

    ).
  • Sexual Dysfunction:
    TRINTELLIX may cause symptoms of sexual dysfunction (
    5.8 Sexual Dysfunction

    Use of serotonergic antidepressants, including TRINTELLIX, may cause symptoms of sexual dysfunction

    . In male patients, serotonergic antidepressant use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, use may result in decreased libido and delayed or absent orgasm.

    It is important for prescribers to inquire about sexual function prior to initiation of TRINTELLIX 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 the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

    ).
Adverse Reactions

The following adverse reactions are discussed in greater detail in other sections of the label.

  • Hypersensitivity
    [see
    4 CONTRAINDICATIONS
    • Hypersensitivity to vortioxetine or any component of the formulation. Hypersensitivity reactions including anaphylaxis, angioedema, and urticaria have been reported in patients treated with TRINTELLIX.
    • 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.

      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.
    • Hypersensitivity to vortioxetine or any components of the TRINTELLIX formulation (4).
    • Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with TRINTELLIX or within 21 days of stopping treatment with TRINTELLIX. Do not use TRINTELLIX within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start TRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue (4).
    ]
  • Clinical Worsening and Suicide Risk
    [see
    5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

    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

    Table 1
    .

    Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in PediatricTRINTELLIX is not approved for use in pediatric patients.and Adult Patients
    Age RangeDrug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1000 Patients Treated
    Increases Compared to Placebo
    <18 years old14 additional patients
    18 to 24 years old5 additional patients
    Decreases Compared to Placebo
    25 to 64 years old1 fewer patient
    ≥65 years old6 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.

    ]
  • Serotonin Syndrome
    [see
    5.2 Serotonin Syndrome

    Serotonergic 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

    . 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

    .

    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.

    ]
  • Increased Risk of Bleeding
    [see
    5.3 Increased Risk of Bleeding

    The use of drugs that interfere with serotonin reuptake inhibition, including TRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the 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

    . Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages.

    Inform patients about the increased risk of bleeding when TRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing TRINTELLIX

    .

    ]
  • Activation of Mania/Hypomania
    [see
    5.4 Activation of Mania/Hypomania

    In patients with bipolar disorder, treating a depressive episode with TRINTELLIX or another antidepressant may precipitate a mixed/manic episode. Symptoms of mania/hypomania were reported in <0.1% of patients treated with TRINTELLIX in premarketing clinical studies. Prior to initiating treatment with TRINTELLIX, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

    ]
  • Discontinuation Syndrome
    [see
    5.5. Discontinuation Syndrome

    Adverse reactions have been reported upon abrupt discontinuation of treatment with TRINTELLIX at doses of 15 mg/day and 20 mg/day

    . A gradual reduction in dosage rather than abrupt cessation 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 (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures.

    ]
  • Angle Closure Glaucoma
    [see
    5.6 Angle Closure Glaucoma

    The pupillary dilation that occurs following use of many antidepressant drugs, including TRINTELLIX, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

    ]
  • Hyponatremia
    [see
    5.7 Hyponatremia

    Hyponatremia has occurred as a result of treatment with serotonergic drugs, including TRINTELLIX. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with serum sodium lower than 110 mmol/L was reported in a subject treated with TRINTELLIX in a premarketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of TRINTELLIX in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

    ]
Drug Interactions
  • Strong inhibitors of CYP2D6: Reduce TRINTELLIX dose by half when coadministered (
    2.5 Use of TRINTELLIX in Known CYP2D6 Poor Metabolizers or in Patients Taking Strong CYP2D6 Inhibitors

    The 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

    .

    ,
    7.1 Drugs Having Clinically Important Interactions with TRINTELLIX
    Table 4: Clinically Important Drug Interactions with TRINTELLIX
    Monoamine Oxidase Inhibitors (MAOIs)
    Clinical Impact
    		The concomitant use of SSRIs and SNRIs including TRINTELLIX with MAOIs increases the risk of serotonin syndrome.
    Intervention
    		Concomitant use of TRINTELLIX is contraindicated:
    • With an MAOI intended to treat psychiatric disorders or within 21 days of stopping treatment with TRINTELLIX.
    • Within 14 days of stopping an MAOI intended to treat psychiatric disorders.
    • In a patient who is being treated with linezolid or intravenous methylene blue.
    Examples
    		selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
    Other Serotonergic Drugs
    Clinical Impact
    		Concomitant use of TRINTELLIX with other serotonergic drugs increases the risk of serotonin syndrome.
    Intervention
    		Monitor for symptoms of serotonin syndrome when TRINTELLIX is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of TRINTELLIX and/or concomitant serotonergic drugs.
    Examples
    		Other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort
    Strong Inhibitors of CYP2D6
    Clinical Impact
    		Concomitant use of TRINTELLIX with strong CYP2D6 inhibitors increases plasma concentrations of vortioxetine.
    Intervention
    		Reduce TRINTELLIX dose by half when a strong CYP2D6 inhibitor is coadministered.
    Examples
    		bupropion, fluoxetine, paroxetine, quinidine
    Strong CYP Inducers
    Clinical Impact
    		Concomitant use of TRINTELLIX with a strong CYP inducer decreases plasma concentrations of vortioxetine.
    Intervention
    		Consider increasing the TRINTELLIX dose when a strong CYP inducer is coadministered. The maximum dose is not recommended to exceed three times the original dose
    Examples
    		rifampin, carbamazepine, phenytoin
    Drugs that Interfere with Hemostasis
    (antiplatelets agents and anticoagulants)
    Clinical Impact
    		Concomitant use of TRINTELLIX with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding.
    Intervention
    		Inform patients of the increased risk of bleeding associated with the concomitant use of TRINTELLIX and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.
    Examples
    		aspirin, clopidogrel, heparin, warfarin
    Drugs Highly Bound to Plasma Protein
    Clinical Impact
    		TRINTELLIX is highly bound to plasma protein. The concomitant use of TRINTELLIX with another drug that is highly bound to plasma protein may increase free concentrations of TRINTELLIX or other tightly-bound drugs in plasma
    .
    Intervention
    		Monitor for adverse reactions and reduce dosage of TRINTELLIX or other protein bound drugs as warranted.
    Examples
    		Warfarin
    ).
  • Strong CYP Inducers: Consider dose increase of TRINTELLIX dose when coadministered for more than 14 days. The maximum recommended dose should not exceed 3 times the original dose (
    2.6 Use of TRINTELLIX in Patients Taking Strong CYP Inducers

    Consider increasing the dose of TRINTELLIX when a strong CYP inducer (e.g., rifampin, carbamazepine, or phenytoin) is coadministered for greater than 14 days. The maximum recommended dose should not exceed three times the original dose. The dose of TRINTELLIX should be reduced to the original level within 14 days, when the inducer is discontinued

    .

    ,
    7.1 Drugs Having Clinically Important Interactions with TRINTELLIX
    Table 4: Clinically Important Drug Interactions with TRINTELLIX
    Monoamine Oxidase Inhibitors (MAOIs)
    Clinical Impact
    		The concomitant use of SSRIs and SNRIs including TRINTELLIX with MAOIs increases the risk of serotonin syndrome.
    Intervention
    		Concomitant use of TRINTELLIX is contraindicated:
    • With an MAOI intended to treat psychiatric disorders or within 21 days of stopping treatment with TRINTELLIX.
    • Within 14 days of stopping an MAOI intended to treat psychiatric disorders.
    • In a patient who is being treated with linezolid or intravenous methylene blue.
    Examples
    		selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
    Other Serotonergic Drugs
    Clinical Impact
    		Concomitant use of TRINTELLIX with other serotonergic drugs increases the risk of serotonin syndrome.
    Intervention
    		Monitor for symptoms of serotonin syndrome when TRINTELLIX is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of TRINTELLIX and/or concomitant serotonergic drugs.
    Examples
    		Other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort
    Strong Inhibitors of CYP2D6
    Clinical Impact
    		Concomitant use of TRINTELLIX with strong CYP2D6 inhibitors increases plasma concentrations of vortioxetine.
    Intervention
    		Reduce TRINTELLIX dose by half when a strong CYP2D6 inhibitor is coadministered.
    Examples
    		bupropion, fluoxetine, paroxetine, quinidine
    Strong CYP Inducers
    Clinical Impact
    		Concomitant use of TRINTELLIX with a strong CYP inducer decreases plasma concentrations of vortioxetine.
    Intervention
    		Consider increasing the TRINTELLIX dose when a strong CYP inducer is coadministered. The maximum dose is not recommended to exceed three times the original dose
    Examples
    		rifampin, carbamazepine, phenytoin
    Drugs that Interfere with Hemostasis
    (antiplatelets agents and anticoagulants)
    Clinical Impact
    		Concomitant use of TRINTELLIX with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding.
    Intervention
    		Inform patients of the increased risk of bleeding associated with the concomitant use of TRINTELLIX and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.
    Examples
    		aspirin, clopidogrel, heparin, warfarin
    Drugs Highly Bound to Plasma Protein
    Clinical Impact
    		TRINTELLIX is highly bound to plasma protein. The concomitant use of TRINTELLIX with another drug that is highly bound to plasma protein may increase free concentrations of TRINTELLIX or other tightly-bound drugs in plasma
    .
    Intervention
    		Monitor for adverse reactions and reduce dosage of TRINTELLIX or other protein bound drugs as warranted.
    Examples
    		Warfarin
    ).
Description

TRINTELLIX is an immediate-release tablet for oral administration that contains the beta (β) polymorph of vortioxetine hydrobromide (HBr), an antidepressant. Vortioxetine HBr is known chemically as 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine, hydrobromide. The empirical formula is C18 H22 N2 S, HBr with a molecular weight of 379.36 g/mol. The structural formula is:

Referenced Image

Vortioxetine HBr is a white to very slightly beige powder that is slightly soluble in water.

Each TRINTELLIX tablet contains 6.355 mg, 12.71 mg or 25.42 mg of vortioxetine HBr equivalent to 5 mg, 10 mg, or 20 mg of vortioxetine, respectively. The inactive ingredients in TRINTELLIX tablets include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate and film coating which consists of hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide red (5 mg and 20 mg) and iron oxide yellow (10 mg).

Pharmacology

The mechanism of the antidepressant effect of vortioxetine is not fully understood, but 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.

Nonclinical Toxicology

Carcinogenesis

Carcinogenicity studies were conducted in which CD-1 mice and Wistar rats were given oral doses of vortioxetine up to 50 and 100 mg/kg/day for male and female mice, respectively, and 40 and 80 mg/kg/day for male and female rats, respectively, for two years. The doses in the two species were approximately 12, 24, 20, and 39 times, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis.

In rats, the incidence of benign polypoid adenomas of the rectum was statistically significantly increased in females at doses 39 times the MRHD, but not at 15 times the MRHD. These were considered related to inflammation and hyperplasia and possibly caused by an interaction with a vehicle component of the formulation used for the study. The finding did not occur in male rats at 20 times the MRHD.

In mice, vortioxetine was not carcinogenic in males or females at doses up to 12 and 24 times, respectively, the MRHD.

Clinical Studies

The efficacy of TRINTELLIX in treatment for MDD was established in six, 6 to 8 week randomized, double-blind, placebo-controlled, fixed-dose studies (including one study in the elderly) and one maintenance study in adult inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD.

How Supplied/Storage & Handling

TRINTELLIX tablets are available as follows:

FeaturesStrengths
5 mg10 mg20 mg
Colorpinkyellowred
Debossment"5" on one side of tablet"10" on one side of tablet"20" on one side of tablet
"TL" on other side of tablet"TL" on other side of tablet"TL" on other side of tablet
Presentations and NDC Codes
Bottles of 3064764-720-3064764-730-3064764-750-30
Bottles of 9064764-720-9064764-730-9064764-750-90
Bottles of 50064764-720-7764764-730-7764764-750-77
Mechanism of Action

The mechanism of the antidepressant effect of vortioxetine is not fully understood, but 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.

Data SourceWe receive information directly from the FDA and PrescriberPoint is updated as frequently as changes are made available
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