DOSAGE FORMS & STRENGTHS SECTION.
3 DOSAGE FORMS AND STRENGTHS TRINTELLIX is available as immediate-release, film-coated tablets in the following strengths: 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 TRINTELLIX is available as 5 mg, 10 mg and 20 mg immediate release tablets (3).
BOXED WARNING SECTION.
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1)]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)]. TRINTELLIX has not been evaluated for use in pediatric patients [see Use in Specific Populations (8.4)]. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.1). Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1). TRINTELLIX has not been evaluated for use in pediatric patients (8.4).
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.
Package/Label Display Panel Trintellix Tablets 20 mg 2430 Approximate Tablets
ADVERSE REACTIONS SECTION.
6 ADVERSE REACTIONS 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)] Angle Closure Glaucoma [see Warnings and Precautions (5.5)] Hyponatremia [see Warnings and Precautions (5.6)] Most common adverse reactions (incidence 5% and at least twice the rate of placebo) were: nausea, constipation and vomiting (6). To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience 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 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in premarketing 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 and 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. 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. Adverse Reactions Reported as Reasons for Discontinuation of Treatment In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received TRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5%, 6%, 8% and 8%, respectively, compared to 4% of placebo-treated patients. Nausea was the most common adverse reaction reported as a reason for discontinuation. Common Adverse Reactions in Placebo-Controlled MDD Studies The most commonly observed adverse reactions in MDD patients treated with TRINTELLIX in 6 to 8 week placebo-controlled studies (incidence 5% and at least twice the rate of placebo) were nausea, constipation and vomiting. Table 2 shows the incidence of common adverse reactions that occurred in 2% of MDD patients treated with any TRINTELLIX dose and at least 2% more frequently than in placebo-treated patients in the 6 to 8 week placebo-controlled studies. Table 2. Common Adverse Reactions Occurring in 2% of Patients Treated with Any TRINTELLIX Dose and at Least 2% Greater Than the Incidence in Placebo-Treated Patients System Organ Class Preferred Term TRINTELLIX 5 mg/day TRINTELLIX 10 mg/day TRINTELLIX 15 mg/day TRINTELLIX 20 mg/day Placebo N=1013 % N=699 % N=449 % N=455 % N=1621 % Gastrointestinal disorders Nausea 21 26 32 32 9 Diarrhea 7 7 10 7 6 Dry mouth 7 7 6 8 6 Constipation 3 5 6 6 3 Vomiting 3 5 6 6 1 Flatulence 1 3 2 1 1 Nervous system disorders Dizziness 6 6 8 9 6 Psychiatric disorders Abnormal dreams <1 <1 2 3 1 Skin and subcutaneous tissue disorders Pruritusincludes pruritus generalized 1 2 3 3 1 Nausea Nausea was the most common adverse reaction and its frequency was dose-related (Table 2). It was usually considered mild or moderate in intensity and the median duration was two weeks. Nausea was more common in females than males. Nausea most commonly occurred in the first week of TRINTELLIX treatment with 15 to 20% of patients experiencing nausea after one to two days of treatment. Approximately 10% of patients taking TRINTELLIX 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies. 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 [see Clinical Studies (14)]. Voluntarily Reported Adverse Reactions of Sexual Dysfunction In the MDD 6 to 8 week controlled trials of TRINTELLIX, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms. These event terms have been aggregated and the overall incidence was as follows. In male patients the overall incidence was 3%, 4%, 4%, 5% in TRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to 2% in placebo. In female patients, the overall incidence was <1%, 1%, <1%, 2% in TRINTELLIX 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to <1% in placebo. Adverse Reactions of Sexual Dysfunction in Patients with Normal Sexual Functioning at Baseline Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in seven placebo-controlled trials. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. The presence or absence of sexual dysfunction among patients entering clinical studies was based on their self-reported ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table 3 shows the incidence of patients that developed TESD when treated with TRINTELLIX or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects. Table 3. ASEX Incidence of Treatment Emergent Sexual DysfunctionIncidence based on number of subjects with sexual dysfunction during the study/number of subjects without sexual dysfunction at baseline. Sexual dysfunction was defined as a subject scoring any of the following on the ASEX scale at two consecutive visits during the study: 1) total score 19; 2) any single item 5; 3) three or more items each with a score 4 TRINTELLIX 5 mg/day N=65:67 Sample size for each dose group is the number of patients (females:males) without sexual dysfunction at baseline TRINTELLIX 10 mg/day N=94:86 TRINTELLIX 15 mg/day N=57:67 TRINTELLIX 20 mg/day N=67:59 Placebo N=135:162 Females 22% 23% 33% 34% 20% Males 16% 20% 19% 29% 14% Adverse Reactions Following Abrupt Discontinuation of TRINTELLIX Treatment Discontinuation symptoms have been prospectively evaluated in patients taking TRINTELLIX 10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and Symptoms (DESS) scale in clinical trials. Some patients experienced discontinuation symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny nose in the first week of abrupt discontinuation of TRINTELLIX 15 mg/day and 20 mg/day. Laboratory Tests TRINTELLIX has not been associated with any clinically important changes in laboratory test parameters in serum chemistry (except sodium), hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies. Hyponatremia has been reported with the treatment of TRINTELLIX [see Warnings and Precautions (5.6)]. In the six month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to TRINTELLIX during the initial 12 week, open-label phase, there were no clinically important changes in lab test parameters between TRINTELLIX and placebo-treated patients. Weight TRINTELLIX had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies. In the six month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to TRINTELLIX during the initial 12 week, open-label phase, there was no significant effect on body weight between TRINTELLIX and placebo-treated patients. Vital Signs TRINTELLIX has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies. Other Adverse Reactions Observed in Clinical Studies The following listing does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Ear and labyrinth disorders vertigo Gastrointestinal disorders dyspepsia Nervous system disorders dysgeusia Vascular disorders flushing 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. 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
INDICATIONS & USAGE SECTION.
1 INDICATIONS AND USAGE TRINTELLIX is indicated for the treatment of major depressive disorder (MDD) in adults (1, 14). 1.1 Major Depressive Disorder TRINTELLIX is indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14) ] .
DRUG ABUSE AND DEPENDENCE SECTION.
9 DRUG ABUSE AND DEPENDENCE TRINTELLIX is not a controlled substance.
DOSAGE & ADMINISTRATION SECTION.
2 DOSAGE AND ADMINISTRATION The recommended starting dose is 10 mg administered orally once daily without regard to meals (2.1). The dose should then be increased to 20 mg/day, as tolerated (2.1). Consider 5 mg/day for patients who do not tolerate higher doses (2.1). 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). The maximum recommended dose is 10 mg/day in known CYP2D6 poor metabolizers (2.6). 2.1 General Instruction for Use 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, because higher doses demonstrated better treatment effects in trials conducted in the United States. 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)]. 2.2 Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depression should be followed by several months or longer of sustained pharmacologic therapy. A maintenance study of TRINTELLIX demonstrated that TRINTELLIX decreased the risk of recurrence of depressive episodes compared to placebo. 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. To avoid these adverse reactions, 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 Adverse Reactions (6)]. 2.4 Switching a Patient to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should 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 should be allowed after stopping TRINTELLIX before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4)]. 2.5 Use of TRINTELLIX with Other MAOIs Such as Linezolid or Methylene Blue Do not start TRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4)]. In some cases, a patient already receiving TRINTELLIX therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, TRINTELLIX should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 21 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with TRINTELLIX may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)]. The risk of administering methylene blue by nonintravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with TRINTELLIX is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)]. 2.6 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 [see Drug Interactions (7.3)]. 2.7 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 [see Drug Interactions (7.3)].
HOW SUPPLIED SECTION.
16 HOW SUPPLIED/STORAGE AND HANDLING TRINTELLIX tablets are available as follows: Trintellix 10 mg, approximately 2520 Tablets per bottle, NDC 55154-0256-8 Trintellix 20 mg, approximately 2430 Tablets per bottle, NDC 55154-0257-8 Storage: Store at 77F (25C); excursions permitted to 59F to 86F (15C to 30C) [see USP Controlled Room Temperature].
SPL UNCLASSIFIED SECTION.
Distributed and marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 Marketed by: Lundbeck Deerfield, IL 60015 Distributed by: Cardinal Health Dublin, OH 43017 L72741019 L72750120 TRINTELLIX is a trademark of H. Lundbeck A/S registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. 2013-2019 Takeda Pharmaceuticals America, Inc. LUN205 R19
11 DESCRIPTION TRINTELLIX is an immediate-release tablet for oral administration that contains the beta () 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: 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).
10 OVERDOSAGE 10.1 Human Experience There is limited clinical trial experience regarding human overdosage with TRINTELLIX. In premarketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of TRINTELLIX. The maximum single dose tested was 75 mg in men. Ingestion of TRINTELLIX in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing. There have been postmarketing reports of overdoses of TRINTELLIX. The most frequently reported symptoms with overdoses up to 80 mg (four times the maximum recommended daily dose) were nausea and vomiting. With overdoses greater than 80 mg, a case of serotonin syndrome in combination with another serotonergic drug, and a case of seizure, have been reported. 10.2 Management of Overdose No specific antidotes for TRINTELLIX are known. In managing overdosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.
SPL MEDGUIDE SECTION.
Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a particularly high risk of having suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions? "What are the possible side effects of TRINTELLIX?" See "What is the most important information I should know about TRINTELLIX?". serotonin syndrome. abnormal bleeding or bruising. hypomania visual problems low levels of salt (sodium) in your blood. This Medication Guide has been approved by the U.S. Food and Drug Administration LUN205 R19Revised: April 2017 MEDICATION GUIDE TRINTELLIX (trin'-TELL-ix) (vortioxetine) Tablets What is the most important information I should know about TRINTELLIX? TRINTELLIX and other antidepressant medicines may cause serious side effects. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. Pay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you: attempts to commit suicide thoughts about suicide or dying feeling agitated, restless, angry or irritable other unusual changes in behavior or mood acting on dangerous impulses new or worse depression trouble sleeping panic attacks acting aggressive, being angry or violent new or worse anxiety an extreme increase in activity or talking (mania) new or worse irritability What is TRINTELLIX? TRINTELLIX is a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD). It is important to talk with your healthcare provider about the risks of treating depression and also the risk of not treating it. You should discuss all treatment choices with your healthcare provider. Talk to your healthcare provider if you do not think that your condition is getting better with TRINTELLIX treatment. 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. take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. Do not take an MAOI within 21 days of stopping TRINTELLIX. Do not start TRINTELLIX if you stopped taking an MAOI in the last 14 days. Before taking TRINTELLIX, tell your healthcare provider about all of your medical conditions, including if you: have liver problems have or had seizures or convulsions have mania or bipolar disorder (manic depression) have low salt (sodium) levels in your blood have or had bleeding problems drink alcohol have any other medical conditions 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). are breastfeeding or plan to breastfeed. It is not known if TRINTELLIX passes into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take TRINTELLIX. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TRINTELLIX and some medicines may interact with each other, may not work as well, or may cause serious side effects when taken together. Especially tell your healthcare provider if you take: medicines used to treat migraine headache (e.g., triptans) medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), buspirone, or antipsychotics MAOIs (including linezolid, an antibiotic) Tramadol or fentanyl over-the-counter supplements such as tryptophan or St. John's Wort nonsteroidal anti-inflammatory drugs (NSAIDs) aspirin warfarin (Coumadin, Jantoven) diuretics rifampin carbamazepine phenytoin quinidine Ask your healthcare provider if you are not sure if you are taking any of these medicines. Before you take TRINTELLIX with any of these medicines, talk to your healthcare provider about serotonin syndrome. See . How should I take TRINTELLIX? Take TRINTELLIX exactly as your healthcare provider tells you to take it. Take TRINTELLIX at about the same time each day. Your healthcare provider may need to change the dose of TRINTELLIX until it is the right dose for you. Do not start or stop taking TRINTELLIX without talking to your healthcare provider first. Suddenly stopping TRINTELLIX when you take higher doses may cause you to have side effects Headache Stiff muscles mood swings sudden outburst of anger dizziness or feeling lightheaded runny nose TRINTELLIX may be taken with or without food. If you take too much TRINTELLIX, call the Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room right away. What are the possible side effects of TRINTELLIX? TRINTELLIX may cause serious side effects, including: A potentially life-threatening problem called serotonin syndrome can happen when medicines such as TRINTELLIX are taken with certain other medicines. Symptoms of serotonin syndrome may include: agitation, hallucinations, coma or other changes in mental status problems controlling your movements or muscle twitching fast heartbeat high or low blood pressure sweating or fever nausea or vomiting diarrhea muscle stiffness or tightness TRINTELLIX may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin, Jantoven), a nonsteroidal anti-inflammatory drug (NSAID), or aspirin. (manic episodes). Symptoms of manic episodes include: greatly increased energy severe problems sleeping racing thoughts talking more or faster than usual unusually grand ideas excessive happiness or irritability reckless behavior eye pain changes in vision swelling or redness in or around the eyeOnly some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Symptoms of this may include: headache, difficulty concentrating, memory changes, confusion, weakness and unsteadiness on your feet. Symptoms of severe or sudden cases of low salt levels in your blood may include: hallucinations (seeing or hearing things that are not real), fainting, seizures and coma. If not treated, severe low sodium levels can cause death. Common side effects in people who take TRINTELLIX include: nausea constipation vomiting These are not all the possible side effects of TRINTELLIX. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store TRINTELLIX? Store TRINTELLIX at room temperature between 59F to 86F (15C to 30C). Keep TRINTELLIX and all medicines out of the reach of children. General information about the safe and effective use of TRINTELLIX. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRINTELLIX for a condition for which it was not prescribed. Do not give TRINTELLIX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TRINTELLIX that is written for healthcare professionals. What are the ingredients in TRINTELLIX? Active ingredient: vortioxetine hydrobromide Inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate and film coating consisting of hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide red (5 mg and 20 mg) and iron oxide yellow (10 mg) Distributed and Marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 Marketed by: Lundbeck, Deerfield, IL 60015 TRINTELLIX is a trademark of H. Lundbeck A/S registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. All other trademarks are the property of their respective owners. 2013-2017 Takeda Pharmaceuticals America, Inc. For more information, go to www.TRINTELLIX.com or call 1-877-TAKEDA-7 (1-877-825-3327).
WARNINGS AND PRECAUTIONS SECTION.
5 WARNINGS AND PRECAUTIONS Serotonin Syndrome has been reported with serotonergic antidepressants (SSRIs, SNRIs, and others), including with TRINTELLIX, both when taken alone, but especially when coadministered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort). If such symptoms occur, discontinue TRINTELLIX and initiate supportive treatment. If concomitant use of TRINTELLIX with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.2). Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase the risk of abnormal bleeding. Patients should be cautioned about the increased risk of bleeding when TRINTELLIX is coadministered with nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation (5.3). Activation of Mania/Hypomania can occur with antidepressant treatment. Screen patients for bipolar disorder (5.4). Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants (5.5). Hyponatremia can occur in association with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (5.6). 5.1 Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a trend toward reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of two months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1. Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Age Range Increases Compared to Placebo <18 14 additional cases 18 - 24 5 additional cases Age Range Decreases Compared to Placebo 25 - 64 1 fewer case 65 6 fewer cases No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that TRINTELLIX is not approved for use in treating bipolar depression. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants including TRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, 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 and intravenous methylene blue). Serotonin syndrome 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/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of TRINTELLIX with MAOIs intended to treat psychiatric disorders is contraindicated. TRINTELLIX should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking TRINTELLIX. TRINTELLIX should be discontinued before initiating treatment with the MAOI [see Contraindications (4), Dosage and Administration (2.4)]. If concomitant use of TRINTELLIX with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with TRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. 5.3 Abnormal 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. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the increased risk of bleeding when TRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Drug Interactions (7.2)]. 5.4 Activation of Mania/Hypomania Symptoms of mania/hypomania were reported in <0.1% of patients treated with TRINTELLIX in premarketing clinical studies. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use TRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. 5.5 Angle Closure Glaucoma 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. 5.6 Hyponatremia Hyponatremia has occurred as a result of treatment with serotonergic drugs. 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 SECTION.
7 DRUG INTERACTIONS Strong inhibitors of CYP2D6: Reduce TRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) is coadministered (2.6, 7.3). Strong CYP Inducers: Consider increasing TRINTELLIX dose when a strong CYP inducer (e.g., rifampin, carbamazepine, or phenytoin) is coadministered for more than 14 days. The maximum recommended dose should not exceed 3 times the original dose (2.7, 7.3). 7.1 CNS Active Agents Monoamine Oxidase Inhibitors Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.2)]. Serotonergic Drugs Based on the mechanism of action of TRINTELLIX and the potential for serotonin toxicity, serotonin syndrome may occur when TRINTELLIX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if TRINTELLIX is coadministered with other serotonergic drugs. Treatment with TRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs [see Warnings and Precautions (5.2)]. Other CNS Active Agents No clinically relevant effect was observed on steady-state lithium exposure following coadministration with multiple daily doses of TRINTELLIX. Multiple doses of TRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that TRINTELLIX (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Details on the potential pharmacokinetic interactions between TRINTELLIX and bupropion can be found in Section 7.3. 7.2 Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of TRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin [see Drug Interactions (7.4)]. Coadministration of aspirin 150 mg/day with multiple daily doses of TRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid [see Drug Interactions (7.4)]. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when TRINTELLIX is initiated or discontinued [see Warnings and Precautions (5.3)]. 7.3 Potential for Other Drugs to Affect TRINTELLIX 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. The maximum dose is not recommended to exceed three times the original dose [see Dosage and Administration (2.5, 2.6)] (Figure 1). Figure 1. Impact of Other Drugs on Vortioxetine PK 7.4 Potential for TRINTELLIX to Affect Other Drugs 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 [see Drug Interactions (7.2)]. Figure 2. Impact of Vortioxetine on PK of Other Drugs
NONCLINICAL TOXICOLOGY SECTION.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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. Mutagenicity Vortioxetine was not genotoxic in the in vitro bacterial reverse mutation assay (Ames test), an in vitro chromosome aberration assay in cultured human lymphocytes, and an in vivo rat bone marrow micronucleus assay. Impairment of Fertility Treatment of rats with vortioxetine at doses up to 120 mg/kg/day had no effect on male or female fertility, which is 58 times the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis.
USE IN SPECIFIC POPULATIONS SECTION.
8 USE IN SPECIFIC POPULATIONS Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and withdrawal in the newborn (8.1). 8.1 Pregnancy Risk Summary 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 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 [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]. 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 [see Warnings and Precautions (5.2)]. 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/m2 basis, 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). 8.2 Lactation 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. 8.4 Pediatric Use Clinical studies on the use of TRINTELLIX in pediatric patients have not been conducted; therefore, the safety and effectiveness of TRINTELLIX in the pediatric population have not been established. 8.5 Geriatric Use No dose adjustment is recommended on the basis of age (Figure 3). Results from a single-dose pharmacokinetic study in elderly (>65 years old) vs young (24 to 45 years old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups. Of the 2616 subjects in clinical studies of TRINTELLIX, 11% (286) were 65 and over, which included subjects from a placebo-controlled study specifically in elderly patients [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.6)]. 8.6 Use in Other Patient Populations 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 (Figure 3) [see Clinical Pharmacology (12.3)]. Figure 3. Impact of Intrinsic Factors on Vortioxetine PK
RECENT MAJOR CHANGES SECTION.
Indications and Usage (1) 10/2018 Contraindications (4) 07/2019
INFORMATION FOR PATIENTS SECTION.
17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Advise patients and their caregivers about the benefits and risks associated with treatment with TRINTELLIX and counsel them in its appropriate use. Advise patients and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document. Suicide Risk 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 [see Boxed Warning, Warnings and Precautions (5.1)]. Discontinuation of Treatment Patients who are on TRINTELLIX 15 mg/day or 20 mg/day may experience headache, muscle tension, mood swings, sudden outburst of anger, dizziness and runny nose if they abruptly stop their medicine. Advise patients not stopping TRINTELLIX without talking to their healthcare provider [see Adverse Reactions (6)]. Concomitant Medication Advise patients to inform their physicians 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, fentanyl, lithium, tramadol, tryptophan supplements, and St. John's Wort supplements [see Warnings and Precautions (5.2), Drug Interactions (7.1, 7.2)]. Abnormal Bleeding Caution patients about the increased risk of abnormal bleeding when TRINTELLIX is given with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [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)]. 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 (5.5)]. 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 (5.6)]. Nausea Advise patients that nausea is the most common adverse reaction, and is dose related. Nausea commonly occurs within the first week of treatment, then decreases in frequency but can persist in some patients. Alcohol A clinical study has shown that TRINTELLIX (single dose of 20 or 40 mg/day) did not increase the impairment of mental and motor skills caused by alcohol. 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)].
CLINICAL STUDIES SECTION.
14 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. Adults (aged 18 years to 75 years) The efficacy of TRINTELLIX in patients aged 18 years to 75 years was demonstrated in five, 6 to 8 week, placebo-controlled studies (Studies 1 to 5 in Table 4). In these studies, patients were randomized to TRINTELLIX 5 mg, 10 mg, 15 mg or 20 mg or placebo once daily. For patients who were randomized to TRINTELLIX 15 mg/day or 20 mg/day, the final doses were titrated up from 10 mg/day after the first week. The primary efficacy measures were the Hamilton Depression Scale (HAMD-24) total score in Study 2 and the Montgomery-Asberg Depression Rating Scale (MADRS) total score in all other studies. In each of these studies, at least one dose group of TRINTELLIX was superior to placebo in improvement of depressive symptoms as measured by mean change from baseline to endpoint visit on the primary efficacy measurement (see Table 4). Subgroup analysis by age, gender or race did not suggest any clear evidence of differential responsiveness. Two studies of the 5 mg dose in the U.S. (not represented in Table 4) failed to show effectiveness. Elderly Study (aged 64 years to 88 years) The efficacy of TRINTELLIX for the treatment of MDD was also demonstrated in a randomized, double-blind, placebo-controlled, fixed-dose study of TRINTELLIX in elderly patients (aged 64 years to 88 years) with MDD (Study 6 in Table 4). Patients meeting the diagnostic criteria for recurrent MDD with at least one previous major depressive episode before the age of 60 years and without comorbid cognitive impairment (Mini Mental State Examination score <24) received TRINTELLIX 5 mg or placebo. Table 4. Primary Efficacy Results of 6 Week to 8 Week Clinical Trials Study No. [Primary Measure] Treatment Group Number of Patients Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. Study 1 [MADRS] Non-US Study TRINTELLIX (5 mg/day)Doses that are statistically significantly superior to placebo after adjusting for multiplicity. 108 34.1 (2.6) -20.4 (1.0) -5.9 (-8.6, -3.2) TRINTELLIX (10 mg/day) 100 34.0 (2.8) -20.2 (1.0) -5.7 (-8.5, -2.9) Placebo 105 33.9 (2.7) -14.5 (1.0) -- Study 2 [HAMD-24] Non-US Study TRINTELLIX (5 mg/day) 139 32.2 (5.0) -15.4 (0.7) -4.1 (-6.2, -2.1) TRINTELLIX (10 mg/day) 139 33.1 (4.8) -16.2 (0.8) -4.9 (-7.0, -2.9) Placebo 139 32.7 (4.4) -11.3 (0.7) -- Study 3 [MADRS] Non-US Study TRINTELLIX (15 mg/day) 149 31.8 (3.4) -17.2 (0.8) -5.5 (-7.7, -3.4) TRINTELLIX (20 mg/day) 151 31.2 (3.4) -18.8 (0.8) -7.1 (-9.2, -5.0) Placebo 158 31.5 (3.6) -11.7 (0.8) -- Study 4 [MADRS] US Study TRINTELLIX (15 mg/day) 145 31.9 (4.1) -14.3 (0.9) -1.5 (-3.9, 0.9) TRINTELLIX (20 mg/day) 147 32.0 (4.4) -15.6 (0.9) -2.8 (-5.1, -0.4) Placebo 153 31.5 (4.2) -12.8 (0.8) -- Study 5 [MADRS] US Study TRINTELLIX (10 mg/day) 154 32.2 (4.5) -13.0 (0.8) -2.2 (-4.5, 0.1) TRINTELLIX (20 mg/day) 148 32.5 (4.3) -14.4 (0.9) -3.6 (-5.9, -1.4) Placebo 155 32.0 (4.0) -10.8 (0.8) -- Study 6 (elderly) [HAMD-24] US and Non-US TRINTELLIX (5 mg/day) 155 29.2 (5.0) -13.7 (0.7) -3.3 (-5.3, -1.3) Placebo 145 29.4 (5.1) -10.3 (0.8) -- TRINTELLIX was superior to placebo on the Clinical Global Impression of Improvement (CGI-I) scale, which is a clinician's impression of how much the patient's clinical condition has improved or worsened relative to baseline on a scale of 1 (very much improved) to 7 (very much worse). Time Course of Treatment Response In the 6 to 8 week placebo-controlled studies, an effect of TRINTELLIX based on the primary efficacy measure was generally observed starting at Week 2 and increased in subsequent weeks with the full antidepressant effect of TRINTELLIX generally not seen until Study Week 4 or later. Figure 4 depicts time course of response in U.S. based on the primary efficacy measure (MADRS) in Study 5. Figure 4. Change from Baseline in MADRS Total Score by Study Visit (Week) in Study 5 Figure 5. Difference from Placebo in Mean Change from Baseline in MADRS Total Score at Week 6 or Week 8 Results (point estimate and unadjusted 95% confidence interval) are from mixed model for repeated measures (MMRM) analysis. In Studies 1 and 6, the primary analysis was not based on MMRM and in Studies 2 and 6 the primary efficacy measure was not based on MADRS. Digit Symbol Substitution Test in Major Depressive Disorder Two, eight week, randomized, double-blind, placebo-controlled studies were conducted to evaluate the effect of TRINTELLIX on the Digit Symbol Substitution Test (DSST) during the treatment of acute MDD. The DSST is a neuropsychological test that most specifically measures processing speed, an aspect of cognitive function that may be impaired in MDD. Patients are asked to match nine symbols with their corresponding number (1 to 9) according to a key; the score is the correct number of matches achieved in 90 seconds. For reference, the mean score for healthy 45 to 54 year-old subjects is 50 (SD=15). Study 7 randomized adult patients meeting the diagnostic criteria for recurrent MDD to receive TRINTELLIX 10 mg, TRINTELLIX 20 mg, or placebo once daily. Study 8 randomized adult patients meeting the diagnostic criteria for recurrent MDD and reporting subjective difficulty concentrating or slow thinking to receive a flexible dose of TRINTELLIX (10 or 20 mg) or placebo once daily. Neither study included patients whose MDD was in remission yet who continued to experience difficulty concentrating or slow thinking. Patients' mean age was 46 (SD=12) and 45 (SD=12) in Study 7 and 8, respectively. In both studies, patients in the TRINTELLIX group had a statistically significantly greater improvement in number of correct responses on the DSST (Table 5); depressed mood as assessed by change from baseline in MADRS total score also improved in both studies. Table 5. Effect of TRINTELLIX on the Digit Symbol Substitution Test (DSST) Study No. Treatment Group Number of Patients Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI) SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. Study 7 TRINTELLIX (10 mg/day)Doses are statistically significantly superior to placebo. 193 42.0 (12.6) 9.0 (0.6) 4.2 (2.5, 5.9) TRINTELLIX (20 mg/day) 204 41.6 (12.7) 9.1 (0.6) 4.3 (2.6, 5.9) Placebo 194 42.4 (13.8) 4.8 (0.6) -- Study 8 TRINTELLIX (10/20 mg/day) 175 42.1 (11.9) 4.6 (0.5) 1.8 (0.3, 3.2) Placebo 167 43.0 (12.3) 2.9 (0.5) -- Maintenance Study In a non-US maintenance study (Study 9 in Figure 6), 639 patients meeting DSM-IV-TR criteria for MDD received flexible doses of TRINTELLIX (5 mg or 10 mg) once daily during an initial 12 week open-label treatment phase; the dose of TRINTELLIX was fixed during Weeks 8 to 12. Three hundred ninety six (396) patients who were in remission (MADRS total score 10 at both Weeks 10 and 12) after open-label treatment were randomly assigned to continuation of a fixed dose of TRINTELLIX at the final dose they responded to (about 75% of patients were on 10 mg/day) during the open-label phase or to placebo for 24 to 64 weeks. Approximately 61% of randomized patients satisfied remission criterion (MADRS total score 10) for at least four weeks (since Week 8), and 15% for at least eight weeks (since Week 4). Patients on TRINTELLIX experienced a statistically significantly longer time to have recurrence of depressive episodes than did patients on placebo. Recurrence of depressive episode was defined as a MADRS total score 22 or lack of efficacy as judged by the investigator. Figure 6. Kaplan-Meier Estimates of Proportion of Patients with Recurrence (Study 9) Prospective Evaluation of Treatment Emergent Sexual Dysfunction (TESD) Two, randomized, double-blind, active-controlled studies were conducted to prospectively compare the incidence of TESD between TRINTELLIX and SSRIs via a validated self-rated measure of sexual function, the Changes in Sexual Functioning Questionnaire Short Form (CSFQ-14). The CSFQ-14 is designed to measure illness- and medication-related changes in sexual functioning that consists of 14 items measuring sexual functioning as a total score. The CSFQ-14 consists of subscales that assess the three phases of the sexual response cycle (desire, arousal, and orgasm). Higher scores on the CSFQ-14 indicate greater sexual function and for reference, a 2-3 point change is considered clinically meaningful. Effect of Switching from SSRI to TRINTELLIX on TESD The effect of TRINTELLIX on TESD induced by prior SSRI treatment in MDD patients whose depressive symptoms were adequately treated was evaluated in an eight-week, randomized, double-blind, active-controlled (escitalopram), flexible-dose study (Study 10). Patients taking citalopram, sertraline, or paroxetine for at least eight weeks duration and who were experiencing sexual dysfunction attributed to their SSRI treatment were switched to TRINTELLIX (n=217) or escitalopram (n=207). For both TRINTELLIX and escitalopram, patients were started on 10 mg, increased to 20 mg at Week 1, followed by flexible dosing. The majority of subjects received the 20 mg dose of TRINTELLIX (65.6%) or the 20 mg dose of escitalopram (71.9%) during the study. Improvement in TESD induced by prior SSRI treatment in subjects switched to TRINTELLIX was superior to the improvement observed in those subjects who switched to escitalopram (2.2 point improvement vs escitalopram on the change from Baseline in CSFQ-14 total score, with 95% confidence interval 0.48 4.02), after eight weeks of treatment, while both drugs maintained the subjects' prior antidepressant response. For change from Baseline in CSFQ-14, see Figure 7 . Figure 7. Change from Baseline in CSFQ-14 Total Score by Study Visit (Week) in Study 10 Effects in Healthy Volunteers with Normal Sexual Functioning at Baseline In a randomized Healthy Volunteer study (Study 11) with 348 subjects aged 18 years to 40 years with normal sexual functioning without the confounding effect of depression, TESD with TRINTELLIX 10 mg (n=85), but not with TRINTELLIX 20 mg (n=91), was statistically significantly less than with paroxetine 20 mg (n=83) [see Adverse Reactions (6.1)]. Paroxetine 20 mg was statistically significantly worse than placebo (n=89), confirming assay sensitivity in this study. For change from Baseline in CSFQ-14, see Figure 8 . Figure 8. Change from Baseline in CSFQ-14 Total Score by Study Visit (Week) in Healthy Volunteers (Study 11)
CLINICAL PHARMACOLOGY SECTION.
12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 Pharmacodynamics Vortioxetine binds with high affinity to the human serotonin transporter (Ki=1.6 nM), but not to the norepinephrine (Ki=113 nM) or dopamine (Ki>1000 nM) transporters. Vortioxetine potently and selectively inhibits reuptake of serotonin (IC50=5.4 nM). Vortioxetine binds to 5-HT3 (Ki=3.7 nM), 5-HT1A (Ki=15 nM), 5-HT7 (Ki=19 nM), 5-HT1D (Ki=54 nM), and 5-HT1B (Ki=33 nM), receptors and is a 5-HT3, 5-HT1D, and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, and 5-HT1A receptor agonist. In humans, the mean 5-HT transporter occupancy, based on the results from two clinical PET studies using 5-HTT ligands ([11C]-MADAM or [11C]-DASB), was approximately 50% at 5 mg/day, 65% at 10 mg/day and approximately 80% at 20 mg/day in the regions of interest. Effect on Cardiac Repolarization The effect of vortioxetine 10 mg and 40 mg administered once daily on QTc interval was evaluated in a randomized, double-blind, placebo-, and active-controlled (moxifloxacin 400 mg), four-treatment-arm parallel study in 340 male subjects. In the study the upper bound of the one-sided 95% confidence interval for the QTc was below 10 ms, the threshold for regulatory concern. The oral dose of 40 mg is sufficient to assess the effect of metabolic inhibition. Effect on Driving Performance In a clinical study in healthy subjects, TRINTELLIX did not impair driving performance, or have adverse psychomotor or cognitive effects following single and multiple doses of 10 mg/day. 12.3 Pharmacokinetics Vortioxetine pharmacological activity is due to the parent drug. The pharmacokinetics of vortioxetine (2.5 mg to 60 mg) are linear and dose-proportional when vortioxetine is administered once daily. The mean terminal half-life is approximately 66 hours, and steady-state plasma concentrations are typically achieved within two weeks of dosing. Absorption The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose (Tmax). Steady-state mean Cmax values were 9, 18, and 33 ng/mL following doses of 5, 10, and 20 mg/day. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed. Distribution The apparent volume of distribution of vortioxetine is approximately 2600 L, indicating extensive extravascular distribution. The plasma protein binding of vortioxetine in humans is 98%, independent of plasma concentrations. No apparent difference in the plasma protein binding between healthy subjects and subjects with hepatic (mild, moderate or severe) or renal (mild, moderate, severe, ESRD) impairment is observed. Metabolism and Elimination Vortioxetine is extensively metabolized primarily through oxidation via cytochrome P450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation. CYP2D6 is the primary enzyme catalyzing the metabolism of vortioxetine to its major, pharmacologically inactive, carboxylic acid metabolite, and poor metabolizers of CYP2D6 have approximately twice the vortioxetine plasma concentration of extensive metabolizers. Following a single oral dose of [14C]-labeled vortioxetine, approximately 59% and 26% of the administered radioactivity was recovered in the urine and feces, respectively as metabolites. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours. The presence of hepatic (mild, moderate or severe) or renal impairment (mild, moderate, severe and ESRD) did not affect the apparent clearance of vortioxetine.
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 [see Adverse Reactions (6.2) ] . 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 Dosage and Administration (2.4), Warnings and Precautions (5.2)]. 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 Dosage and Administration (2.5), Warnings and Precautions (5.2)]. 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).