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

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 ).

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.

The recommended starting dose is 10 mg administered orally once daily without regard to meals. The dose should then be increased to 20 mg/day, as tolerated. Consider 5 mg/day for patients who do not tolerate higher doses. TRINTELLIX can be discontinued abruptly. However, it is recommended that doses of 15 mg/day or 20 mg/day be reduced to 10 mg/day for one week prior to full discontinuation if possible. The maximum recommended dose is 10 mg/day in known CYP2D6 poor metabolizers

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

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

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

Switching a Patient to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days must elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with TRINTELLIX to avoid the risk of Serotonin Syndrome . Conversely, at least 21 days must elapse after stopping TRINTELLIX before starting an MAOI intended to treat psychiatric disorders

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

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 .

Serotonin Syndrome : Increased risk when coadministered with other serotonergic agents, but also when taken alone. If it occurs, discontinue TRINTELLIX and serotonergic agents and initiate supportive measures. Increased Risk of Bleeding : Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, or other drugs that affect coagulation may increase risk. Activation of Mania/Hypomania : Screen patients for bipolar disorder. Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. Hyponatremia : Can occur in association with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Sexual Dysfunction: TRINTELLIX may cause symptoms of sexual dysfunction

Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1 . Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric TRINTELLIX is not approved for use in pediatric patients. and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in adolescents and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that the use of antidepressants can delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for all approved populations for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing TRINTELLIX, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts and behaviors

Serotonin Syndrome Serotonergic antidepressants, including TRINTELLIX, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, meperidine, methadone, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of TRINTELLIX with MAOIs is contraindicated. In addition, do not initiate TRINTELLIX in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking TRINTELLIX, discontinue TRINTELLIX before initiating treatment with the MAOI . Monitor all patients taking TRINTELLIX for the emergence of serotonin syndrome. Discontinue treatment with TRINTELLIX and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of TRINTELLIX with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms

Increased Risk of Bleeding The use of drugs that interfere with serotonin reuptake inhibition, including TRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs or SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage . Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding when TRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing TRINTELLIX

Activation of Mania/Hypomania In patients with bipolar disorder, treating a depressive episode with TRINTELLIX or another antidepressant may precipitate a mixed/manic episode. Symptoms of mania/hypomania were reported in <0.1% of patients treated with TRINTELLIX in premarketing clinical studies. Prior to initiating treatment with TRINTELLIX, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.5. Discontinuation Syndrome Adverse reactions have been reported upon abrupt discontinuation of treatment with TRINTELLIX at doses of 15 mg/day and 20 mg/day . A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible . Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures

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

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

Sexual Dysfunction Use of serotonergic antidepressants, including TRINTELLIX, may cause symptoms of sexual dysfunction . In male patients, serotonergic antidepressant use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of TRINTELLIX and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

Strong inhibitors of CYP2D6: Reduce TRINTELLIX dose by half when coadministered. 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

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

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