Trintellix

1 INDICATIONS AND USAGE TRINTELLIX is indicated for the treatment of major depressive disorder (MDD) in adults. TRINTELLIX is indicated for the treatment of major depressive disorder (MDD) in adults ( 1 , 14 ).

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 ( 2.5 ). 2.1 Recommended Dosage The recommended starting dose is 10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses [see Clinical Studies (14) ] . 2.2 Screen for Bipolar Disorder Prior to Starting TRINTELLIX Prior to initiating treatment with TRINTELLIX or another antidepressant, screen patients for personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.4) ] . 2.3 Discontinuing Treatment Although TRINTELLIX can be abruptly discontinued, in placebo-controlled trials patients experienced transient adverse reactions such as headache and muscle tension following abrupt discontinuation of TRINTELLIX 15 mg/day or 20 mg/day. It is recommended that the dose be decreased to 10 mg/day for one week before full discontinuation of TRINTELLIX 15 mg/day or 20 mg/day [see Warnings and Precautions (5.5) and 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 must elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with TRINTELLIX to avoid the risk of Serotonin Syndrome [see Warnings and Precautions (5.2) ] . Conversely, at least 21 days must elapse after stopping TRINTELLIX before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4) ] . 2.5 Use of TRINTELLIX in Known CYP2D6 Poor Metabolizers or in Patients Taking Strong CYP2D6 Inhibitors The maximum recommended dose of TRINTELLIX is 10 mg/day in known CYP2D6 poor metabolizers. Reduce the dose of TRINTELLIX by one-half when patients are receiving a CYP2D6 strong inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) concomitantly. The dose should be increased to the original level when the CYP2D6 inhibitor is discontinued [see Drug Interactions (7.1) , Use in Specific Populations (8.6) ] . 2.6 Use of TRINTELLIX in Patients Taking Strong CYP Inducers Consider increasing the dose of TRINTELLIX when a strong CYP inducer (e.g., rifampin, carbamazepine, or phenytoin) is coadministered for greater than 14 days. The maximum recommended dose should not exceed three times the original dose. The dose of TRINTELLIX should be reduced to the original level within 14 days, when the inducer is discontinued [see Drug Interactions (7.1) ] .

3 DOSAGE FORMS AND STRENGTHS TRINTELLIX is available as: • 5 mg: pink, almond shaped biconvex film coated tablet, debossed with "5" on one side and "TL" on the other side • 10 mg: yellow, almond shaped biconvex film coated tablet, debossed with "10" on one side and "TL" on the other side • 20 mg: red, almond shaped biconvex film coated tablet, debossed with "20" on one side and "TL" on the other side Tablets: 5 mg, 10 mg, and 20 mg ( 3 ).

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 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 ).

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) ] • 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) ] 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 America, Inc. 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 trials of another drug and may not reflect the rates observed in clinical practice. Patient Exposure TRINTELLIX was evaluated for safety in 5,852 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre- and postmarketing clinical studies; 2,616 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 2,586 patients were exposed to at least one dose of TRINTELLIX in open-label studies, 1,727 were exposed to TRINTELLIX for 6 months and 885 were exposed for at least 1 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: 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 Pruritus includes 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 f …

7 DRUG INTERACTIONS • Strong inhibitors of CYP2D6: Reduce TRINTELLIX dose by half when coadministered ( 2.5 , 7.1 ). • Strong CYP Inducers: Consider dose increase of TRINTELLIX dose when coadministered for more than 14 days. The maximum recommended dose should not exceed 3 times the original dose ( 2.6 , 7.1 ). 7.1 Drugs Having Clinically Important Interactions with TRINTELLIX Table 4: Clinically Important Drug Interactions with TRINTELLIX Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of SSRIs and SNRIs including TRINTELLIX with MAOIs increases the risk of serotonin syndrome. Intervention Concomitant use of TRINTELLIX is contraindicated: • With an MAOI intended to treat psychiatric disorders or within 21 days of stopping treatment with TRINTELLIX. • Within 14 days of stopping an MAOI intended to treat psychiatric disorders. • In a patient who is being treated with linezolid or intravenous methylene blue. [see Dosage and Administration (2.4) , Contraindications (4) , Warnings and Precautions (5.2) ] Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact Concomitant use of TRINTELLIX with other serotonergic drugs increases the risk of serotonin syndrome. Intervention Monitor for symptoms of serotonin syndrome when TRINTELLIX is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of TRINTELLIX and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2) ] . Examples Other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort Strong Inhibitors of CYP2D6 Clinical Impact Concomitant use of TRINTELLIX with strong CYP2D6 inhibitors increases plasma concentrations of vortioxetine. Intervention Reduce TRINTELLIX dose by half when a strong CYP2D6 inhibitor is coadministered [see Dosage and Administration (2.5) ] . Examples bupropion, fluoxetine, paroxetine, quinidine Strong CYP Inducers Clinical Impact Concomitant use of TRINTELLIX with a strong CYP inducer decreases plasma concentrations of vortioxetine. Intervention Consider increasing the TRINTELLIX dose when a strong CYP inducer is coadministered. The maximum dose is not recommended to exceed three times the original dose [see Dosage and Administration (2.6) ]. Examples rifampin, carbamazepine, phenytoin Drugs that Interfere with Hemostasis (antiplatelets agents and anticoagulants) Clinical Impact Concomitant use of TRINTELLIX with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. Intervention Inform patients of the increased risk of bleeding associated with the concomitant use of TRINTELLIX and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warnings and Precautions (5.3) , Drug Interactions (7.2) ] . Examples aspirin, clopidogrel, heparin, warfarin Drugs Highly Bound to Plasma Protein Clinical Impact TRINTELLIX is highly bound to plasma protein. The concomitant use of TRINTELLIX with another drug that is highly bound to plasma protein may increase free concentrations of TRINTELLIX or other tightly-bound drugs in plasma . Intervention Monitor for adverse reactions and reduce dosage of TRINTELLIX or other protein bound drugs as warranted [see Drug Interactions (7.2) ] . Examples Warfarin 7.2 Effect of TRINTELLIX on Other Drugs 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 [see Clinical Pharmacology (12.3) ] . 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 ( …

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 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. Risk Summary Based on data from published observational studies, exposure to SSRIs or SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [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 ≥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 ] . 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) ]. 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, hypo …

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.

11 DESCRIPTION TRINTELLIX is an immediate-release tablet for oral administration that contains the beta (β) polymorph of vortioxetine hydrobromide (HBr), an antidepressant. Vortioxetine HBr is known chemically as 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine, hydrobromide. The empirical formula is C 18 H 22 N 2 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). Chemical Structure

10 OVERDOSAGE 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. No specific antidotes for TRINTELLIX are known. Consider contacting the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING TRINTELLIX tablets are available as follows: Features Strengths 5 mg 10 mg 20 mg Color pink yellow red Debossment "5" on one side of tablet "10" on one side of tablet "20" on one side of tablet "TL" on other side of tablet "TL" on other side of tablet "TL" on other side of tablet Presentations and NDC Codes Bottles of 30 64764-720-30 64764-730-30 64764-750-30 Bottles of 90 64764-720-90 64764-730-90 64764-750-90 Bottles of 500 64764-720-77 64764-730-77 64764-750-77 Store at 77°F (25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature].