vortioxetine 5 MG Oral Tablet [Trintellix]

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 ).

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) ] .

WARNINGS AND PRECAUTIONS Serotonin Syndrome : Increased risk when coadministered with other serotonergic agents, but also when taken alone. If it occurs, discontinue TRINTELLIX and serotonergic agents and initiate supportive measures ( 5.2 ). Increased Risk of Bleeding : Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs, warfarin, or other drugs that affect coagulation may increase risk ( 5.3 ). Activation of Mania/Hypomania : 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 ( 5.6 ). Hyponatremia : Can occur in association with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) ( 5.7 ). Sexual Dysfunction: TRINTELLIX may cause symptoms of sexual dysfunction ( 5.8 ). 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1 . Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in 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. 5.2 Serotonin Syndrome Serotonergic antidepressants, including TRINTELLIX, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, meperidine, methadone, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) , Drug Interactions (7.1) ] . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of TRINTELLIX with MAOIs is contraindicated. In addition, do not initiate TRINTELLIX in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking TRINTELLIX, discontinue TRINTELLIX before initiating treatment with the MAOI [see Contraindications (4) , Drug Interactions (7.1) ] . Monitor all patients taking TRINTELLIX for the emergence of serotonin syndrome. Discontinue treatment with TRINTELLIX and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of TRINTELLIX with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Increased Risk of Bleeding The use of drugs that interfere with serotonin reuptake inhibition, including TRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs or SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1) ] . Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding when TRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding. For patients taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing TRINTELLIX [see Drug Interactions (7.1) ] . 5.4 Activation of Mania/Hypomania In patients with bipolar disorder, treating a depressive episode with TRINTELLIX or another antidepressant may precipitate a mixed/manic episode. Symptoms of mania/hypomania were reported in <0.1% of patients treated with TRINTELLIX in premarketing clinical studies. Prior to initiating treatment with TRINTELLIX, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 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 [see Adverse Reactions (6.1) ] . A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.3) ]. Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. 5.6 Angle Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including TRINTELLIX, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.7 Hyponatremia Hyponatremia has occurred as a result of treatment with serotonergic drugs

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 ).

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.