Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

TRINTELLIX (NDA-204447)

(VORTIOXETINE HYDROBROMIDE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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08/23/2023 (SUPPL-26)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

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 [see Adverse Reactions (6)].

Antidepressants, such as TRINTELLIX, increase the risk of suicidal thoughts and behaviors in pediatric patients [see Boxed Warning and Warnings and Precautions (5.1)].

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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

What is the most important information I should know about TRINTELLIX? TRINTELLIX can cause serious side effects, including:

Increased risk of suicidal thoughts and actions. TRINTELLIX and other antidepressant medicines increase the risk of suicidal thoughts and actions in people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. TRINTELLIX is not for use in children.
- Depression or other mental illnesses are the most important causes of suicidal thoughts or actions.
  How can I watch for and try to prevent suicidal thoughts and actions?
- Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings, of if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed.

…

What is TRINTELLIX?

TRINTELLIX is a prescription medicine used in adults to treat a certain type of depression called Major Depressive Disorder (MDD).

TRINTELLIX has not been shown to be safe and effective for use in children.

Do not take TRINTELLIX if you:

are allergic to vortioxetine or any of the ingredients in TRINTELLIX. See the end of this Medication Guide for a complete list of ingredients in TRINTELLIX

are taking, or have stopped taking within the last 14 days
, a medicine called a Monoamine Oxidase Inhibitor (MAOI), including the antibiotic linezolid or intravenous methylene blue

…

Especially tell your healthcare provider if you take:

medicines used to treat migraine headache called triptans

tricyclic antidepressants
lithium
tramadol, fentanyl, meperidine, methadone, or other opioids
tryptophan
buspirone
St. John’s Wort
medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin
diuretics
medicines used to treat mood, anxiety, psychotic or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)
medicines used to treat seizures or convulsions

…

08/18/2023 (SUPPL-27)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Serotonin Syndrome

(Additions and/or revisions underlined)

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 [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.

5.3 Increased Risk of Bleeding

(Additions and/or revisions underlined)

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 [see Use in Specific Populations (8.1)]. 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 [see Drug Interactions (7.1)].

6 Adverse Reactions

(Additions and/or revisions underlined)

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

· Hypersensitivity [see Contraindications (4)]

· Clinical Worsening and Suicide Risk [see Warnings and Precautions (5.1)]

· Serotonin Syndrome [see Warnings and Precautions (5.2)]

· Increased Risk of Bleeding [see Warnings and Precautions (5.3)]

· Activation of Mania/Hypomania [see Warnings and Precautions (5.4)]

· Discontinuation Syndrome [see Warnings and Precautions (5.5)]

· Angle Closure Glaucoma [see Warnings and Precautions (5.6)]

· Hyponatremia [see Warnings and Precautions (5.7)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

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

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

Pregnancy Exposure Registry

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 [see Warnings and Precautions (5.3) and Clinical Considerations].

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 [see Clinical Considerations]. Vortioxetine administered to pregnant rats and rabbits during the period of organogenesis at doses greater than or equal to 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 greater than or equal to 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 greater than or equal to 20 times the MRHD. These effects were not seen at 5 times the MRHD [see Data]. 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 [see Data].

Maternal Adverse Reactions

Use of TRINTELLIX in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.3)].

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning, Warnings and Precautions (5.1)].

Concomitant Medication

Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter medications because of a potential for interactions.

Instruct patients not to take TRINTELLIX with an MAOI or within 14 days of stopping an MAOI and to allow 21 days after stopping TRINTELLIX before starting an MAOI [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.2), Drug Interactions (7.1)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of TRINTELLIX and triptans, tricyclic antidepressants, opioids, lithium, tryptophan supplements, busipirone, and St. John’s Wort and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions (5.2), Drug Interactions (7.1, 7.2)]. Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

09/20/2021 (SUPPL-24)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.8 Sexual Dysfunction

(Newly added subsection)

Use of serotonergic antidepressants, including TRINTELLIX, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. 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.

6 Adverse Reactions

6.1 Clinical Studies Experience

(Additions and/or revisions underlined)

…

Sexual Dysfunction

Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or comorbid conditions, but they may also be consequences of pharmacologic treatment, including TRINTELLIX. In addition to the data from the MDD studies mentioned below, TRINTELLIX has been prospectively assessed for its effects in MDD patients with existing TESD induced by prior SSRI treatment and in healthy adults with normal sexual function at baseline [see Clinical Studies (14)].

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Additions and/or revisions underlined)

…

Sexual problems (dysfunction). Taking TRINTELLIX may cause sexual problems.

Symptoms in males may include:

Delayed ejaculation or inability to have an ejaculation
Decreased sex drive
Problems getting or keeping an erection

Symptoms in females may include:

Decreased sex drive
Delayed orgasm or inability to have an orgasm

Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with TRINTELLIX. There may be treatments your healthcare provider can suggest.

…

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

…

Sexual Dysfunction

Advise patients that use of TRINTELLIX may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.8)].

…

01/22/2021 (SUPPL-21)

Approved Drug Label (PDF)

Boxed Warning

(Box Warning in supplement 21 has been revised; see underlined text)

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

Increased risk of suicidal thinking and behavior in pediatric and young adult patients taking antidepressants.
Closely monitor for worsening and emergence of suicidal thoughts and behaviors (5.1).
TRINTELLIX is not approved for use in pediatric patients (8.4).

5 Warnings and Precautions

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

(Additions and/or revisions underlined)

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 1000 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 Pediatric and Adult Patients

…

TRINTELLIX is not approved for use in pediatric 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.

5.3 Increased Risk of Bleeding

(Subsection title revised)

(Additions and/or revisions underlined)

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

5.4 Activation of Mania/Hypomania

(Additions and/or revisions underlined)

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.

5.5 Discontinuation Syndrome

(Newly added subsection)

Adverse reactions have been reported upon abrupt discontinuation of treatment with TRINTELLIX at doses of 15 mg/day and 20 mg/day [see Adverse Reactions (6.1)]. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.3)].

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.

5.7 Hyponatremia

(Additions and/or revisions underlined)

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.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions underlined)

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/.

…

8.4 Pediatric Use

(Additions and/or revisions underlined)

The safety and effectiveness of TRINTELLIX have not been established in pediatric patients for the treatment of MDD.

Efficacy was not established in an 8-week, randomized, double-blind, placebo- controlled, active-reference study in 615 pediatric patients 12 to 17 years of age with MDD. The primary efficacy endpoint was change from double-blind baseline to Week 8 on the Children’s Depression Rating Scale-Revised version. The effect of treatment with vortioxetine was not significantly different from placebo (placebo-subtracted difference of 0.21 (95% CI: -2.41, 2.82; p=0.88). In this age group, adverse reactions to TRINTELLIX were generally similar to those reported in adults.

Antidepressants, such as TRINTELLIX, increase the risk of suicidal thoughts and behaviors in pediatric patients [see the Boxed Warning and Warnings and Precautions (5.1)].

Juvenile Animal Toxicity Data

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

(Extensive changes; please refer to label)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

See FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors

Concomitant Medication

Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter medications because of a potential for interactions.

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of TRINTELLIX and triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan supplements, busipirone, and St. John’s Wort and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [see Warnings and Precautions (5.2), Drug Interactions (7.1, 7.2)]. Instruct patients to contact their health care provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome.

Increased Risk of Bleeding

Inform patients about the concomitant use of TRINTELLIX with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation because combined use has been associated with an increased risk of bleeding. Advise patients to inform their health care provider if they are taking or planning to take any prescription or over-the-counter medications that increase the risk of bleeding [see Warnings and Precautions (5.3)].

Activation of Mania/Hypomania

Advise patients and their caregivers to look for signs of activation of mania/hypomania

[see Warnings and Precautions (5.4)].

Discontinuation of Treatment

Advise patients not to abruptly stop taking TRINTELLIX without first talking to their healthcare provider. Patients should be aware that discontinuation effects may occur when stopping TRINTELLIX and they should monitor for discontinuation symptoms [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].

Angle Closure Glaucoma

Patients should be advised that taking TRINTELLIX can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre- existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.6)].

Hyponatremia

Advise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking TRINTELLIX [see Warnings and Precautions (5.7)].

Nausea

Advise patients that nausea is one of the most common adverse reactions, and is dose related. Nausea commonly occurs within the first week of treatment, then decreases in frequency but can persist in some patients [see Adverse Reactions (6.1)].

Allergic Reactions

Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing.

Pregnancy

Advise a pregnant woman or a woman planning to become pregnant that TRINTELLIX may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN) [see Use in Specific Populations (8.1)]. Advise the patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRINTELLIX during pregnancy [see Use in Specific Populations (8.1)].

01/22/2021 (SUPPL-22)

Approved Drug Label (PDF)

6 Adverse Reactions

(Additions and/or revisions underlined)

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

Hypersensitivity [see Contraindications (4)]
Clinical Worsening and Suicide Risk [see Warnings and Precautions (5.1)]
Serotonin Syndrome [see Warnings and Precautions (5.2)]
Abnormal Bleeding [see Warnings and Precautions (5.3)]
Activation of Mania/Hypomania [see Warnings and Precautions (5.4)]
Discontinuation Syndrome [see Warnings and Precautions (5.5)]
Angle Closure Glaucoma [see Warnings and Precautions (5.6)]
Hyponatremia [see Warnings and Precautions (5.7)]

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

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

Skin and subcutaneous tissue disorders — rash, generalized rash, hyperhidrosis

7 Drug Interactions

7.3 Interference with Urine Enzyme Immunoassays for Methadone

(Newly added subsection)

False positive results in urine enzyme immunoassays for methadone have been reported in patients who have taken vortioxetine. An alternative analytical technique (e.g., chromatographic methods) should be considered to confirm positive methadone urine drug screen results.

11/13/2020 (SUPPL-20)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Studies Experience

(Additions and/or revisions underlined)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

Patient Exposure

TRINTELLIX was evaluated for safety in 5852 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre- and postmarketing clinical studies; 2616 of those patients were exposed to TRINTELLIX in 6 to 8 week, placebo-controlled studies at doses ranging from 5 mg to 20 mg once daily; 204 patients were exposed to TRINTELLIX in a 24 to 64 week placebo-controlled maintenance study at doses of 5 mg to 10 mg once daily; and 429 patients were exposed to TRINTELLIX in a 32 week placebo-controlled maintenance study in the U.S. at doses of 5 mg, 10 mg, and 20 mg, once daily. Patients from the 6 to 8 week studies continued into 12 month open-label studies. A total of 2586 patients were exposed to at least one dose of TRINTELLIX in open-label studies, 1727 were exposed to TRINTELLIX for six months and 885 were exposed for at least one year.

…

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

Gastrointestinal system — acute pancreatitis

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

Metabolic disorders — weight gain

Nervous system disorders — seizure

Skin and subcutaneous tissue disorders — rash, generalized rash

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

7 Drug Interactions

7.1 Drugs Having Clinically Important Interactions with TRINTELLLIX

(Subsection title revised)

(Extensive changes; please refer to label)

7.2 Effect of TRINTELLIX on Other Drugs

(Subsection title revised)

(Additions and/or revisions underlined)

…

Highly Protein Bound Drugs

…

8 Use in Specific Populations

8.6 CYP2D6 Poor Metabolizers

(Subsection title revised)

(Additions and/or revisions underlined)

Dosage reduction is recommended in patients known to be poor CYP2D6 metabolizers because these patients have higher vortioxetine plasma concentrations than extensive CYP2D6 metabolizers [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

07/23/2019 (SUPPL-18)

Approved Drug Label (PDF)

4 Contraindications

(additions are underlined)

· 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

6 Adverse Reactions

6.2 Postmarketing Experience

(additions are underlined)

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

Metabolic disorders — weight gain

Nervous system disorders — seizure

Skin and subcutaneous tissue disorders — rash, generalized rash

Gastrointestinal System — acute pancreatitis

10/19/2018 (SUPPL-17)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Studies Experience

(Additions and/or revisions are underlined)

Sexual Dysfunction

Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be consequences of pharmacologic treatment. In addition to the data from the MDD studies mentioned below, TRINTELLIX has been prospectively assessed for its effects in MDD patients with existing TESD induced by prior SSRI treatment and in healthy adults with normal sexual function at baseline.

Voluntarily Reported Adverse Reactions of Sexual Dysfunction

Adverse Reactions of Sexual Dysfunction in Patients with Normal Sexual Functioning at Baseline

04/11/2017 (SUPPL-13)

Approved Drug Label (PDF)

6 Adverse Reactions

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

(Additions and/or revisions are underlined)

• Angle Closure Glaucoma

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during post-approval 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.

Nervous system disorders — seizure

Skin and subcutaneous tissue disorders — rash, generalized rash

7 Drug Interactions

7.3 Potential for Other Drugs to Affect TRINTELLIX

(Additions and/or revisions are underlined)

Reduce TRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the TRINTELLIX dose when a strong CYP inducer (e.g., rifampin, carbamazepine, phenytoin) is coadministered…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE TRINTELLIX (trin’-TELL-ix) (vortioxetine) Tablets

(Additions and/or revisions are underlined)

Especially tell your healthcare provider if you take:

• rifampin

04/03/2017 (SUPPL-8)

Approved Drug Label (PDF)

7 Drug Interactions

7.4 Potential for TRINTELLIX to Affect Other Drugs

(additions underlined)

No dose adjustment for the comedications is needed when TRINTELLIX is coadministered with a substrate of CYP1A2 (e.g., duloxetine, caffeine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinide), CYP2C9 (e.g., S-warfarin, tolbutamide), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine, dextromethorphan), CYP3A4/5 (e.g., budesonide, midazolam), P-gp (e.g., digoxin), BCRP (e.g., methotrexate), OATP1B1/3 (e.g., rosuvastatin) and OCT2 (e.g., metformin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary.

Vortioxetine and its metabolite(s) are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, P-gp, BCRP, BSEP, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 and OCT2. As such, no clinically relevant interactions with drugs metabolized/transported by these CYP enzymes or transporters would be expected.

In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of TRINTELLIX is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of TRINTELLIX with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2). Because vortioxetine is highly bound to plasma protein, coadministration of TRINTELLIX with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of TRINTELLIX (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed.

8 Use in Specific Populations

8.1 Pregnancy

Data

(additions underlined)

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 post-marketing 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."

8.6 Use in Other Patient Populations

(subsection revised, addition underlined)

No dose adjustment of TRINTELLIX on the basis of race, gender, ethnicity, or renal function (from mild renal impairment to end-stage renal disease) is necessary. In addition, the same dose can be administered in patients with mild to severe hepatic impairment.

03/10/2017 (SUPPL-9)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion, please refer to label)

8.2 Lactation

(PLLR conversion)

Risk Summary

There is no information regarding the presence of vortioxetine in human milk, the effects on the breastfed infant, or the effects on milk production. Vortioxetine is present in rat milk [see Data]. The developmental and health benefits of breastfeeding should be considered 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.

Data

Animal Data

Administration of [14C]-vortioxetine to lactating rats at an oral dose of 20 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis, resulted in drug-related material in milk secretion. Milk to plasma ratio in lactating rats was 1, 1.2, 0.5, and 0.5 at 2, 6, 24, and 72 hours post dose.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(additions underlined)

Pregnancy

Advise a pregnant woman or a woman planning to become pregnant that TRINTELLIX may cause withdrawal symptoms in the newborn or persistent pulmonary hypertension of the newborn (PPHN).

Medication Guide

(additions underlined)

…

Before taking TRINTELLIX, tell your healthcare provider about all of your medical conditions, including if you:

…

are pregnant or plan to become pregnant. It is not known if TRINTELLIX will harm your unborn baby. Taking TRINTELLIX while pregnant in your third trimester may cause your newborn baby to have withdrawal symptoms that causes a certain type of breathing problem called Persistent Pulmonary Hypertension of the Newborn (PPHN).

10/17/2016 (SUPPL-12)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience (addition underlined)

Gastrointestinal System — acute pancreatitis

08/30/2016 (SUPPL-11)

Approved Drug Label (PDF)

6 Adverse Reactions

Postmarketing Experience

The following adverse reactions have been identified during post-approval 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.

Metabolic disorders — weight gain