Vortioxetine

298.44568

298.45

1308068-626-2

3O2K1S3WQV

N06AX26|N - Nervous system

2933599090

40.6

4.2

1.16

210.7±28.7 °C

1.643

In water, 7.8 mg/L at 25 deg C (est)

Store at 77 deg F (25 deg C); excursions permitted to 59 deg F to 86 deg F (15 deg C to 30 deg C).

5.43X10-8 mm Hg at 25 deg C (est)

Henry's Law constant = 8.03X10-11 atm-cu m/mol at 25 °C (est)

pKa = 8.84 (secondary amine) (est)

White to very slightly beige powder; slightly soluble in water /Vortioxetine hydrogen bromide/|Hydroxyl radical reaction rate constant = 2.14X10-11 cu cm/molec-sec at 25 °C (est)

stable if stored as directed /Vortioxetine hydrobromide/

P201, P202, P260, P264, P270, P281, P308+P313, P309+P311, P314, P405, P501

H361

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including vortioxetine hydrobromide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Vortioxetine hydrobromide/

|Warning|H361 (100%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]|P201, P202, P260, P264, P270, P281, P308+P313, P309+P311, P314, P405, and P501|Aggregated GHS information provided by 6 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Eye protection: chemical safety goggles. /Vortioxetine hydrobromide/|Protection of hands: chemical-resistant rubber gloves. /Vortioxetine hydrobromide/|Breathing equipment: NIOSH/MSHA-approved respirator. /Vortioxetine hydrobromide/

Suitable extinguishing agents: water spray, carbon dioxide, dry chemical powder or foam. Protective equipment: wear self-contained breathing apparatus and protective clothing to prevent contact with skin and eyes. /Vortioxetine hydrobromide/

After Inhalation: cordon off area of spill; wear self-contained breathing apparatus, protective clothing and heavy rubber gloves. Measures for cleaning/collecting: absorb solutions with finely-powdered liquid-binding material (diatomite, universal binders); decontaminate surfaces and equipment by scrubbing with alcohol; dispose of contaminated material. /Vortioxetine hydrobromide/

Information for safe handling: avoid inhalation and contact with skin, eyes and clothing; material may be an irritant. /Vortioxetine hydrobromide/

The most commonly reported adverse effects during clinical trials were nausea, diarrhea, and dry mouth. The FDA label includes a blackbox warning for the following risks and complications: serotonin syndrome, especially when combined with other serotonergic agents; increased risk of abnormal bleeding, especially when combined with NSAIDs, aspirin, or other drugs that affect coagulation; activation of mania/hypomania; hyponatremia; and suicidal thoughts and behaviour in children, adolescents, and young adults.|IDENTIFICATION AND USE: Vortioxetine is a white to very slightly beige powder formulated into film-coated tablets. It is used for the management of major depressive disorders in adults. HUMAN EXPOSURE AND TOXICITY: There is limited clinical trial experience regarding human overdosage with vortioxetine. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of vortioxetine. The maximum single dose tested was 75 mg in men. Ingestion of vortioxetine 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. Toxicity may also occur at therapeutic dosage levels of vortioxetine. Potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants, including vortioxetine, when used alone, but particularly with concurrent use of other serotonergic drugs (including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists ("triptans"), tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort (Hypericum perforatum)) and with drugs that impair the metabolism of serotonin (particularly monoamine oxidase (MAO) inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue). Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, and hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, and incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, and diarrhea). Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated. Use of an MAO inhibitor intended to treat psychiatric disorders within 3 weeks of vortioxetine discontinuance also is contraindicated. Vortioxetine also should not be initiated in patients who are being treated with other MAO inhibitors such as linezolid or IV methylene blue. If concurrent therapy with vortioxetine and other serotonergic drugs is clinically warranted, the patient should be made aware of the potential increased risk for serotonin syndrome, particularly during initiation of therapy or when dosage is increased. 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. Vortioxetine was not genotoxic in an in vitro chromosome aberration assay in cultured human lymphocytes. ANIMAL STUDIES: The acute oral single dose toxicity of vortioxetine is relatively low with a maximum tolerated dose (MTD) in mice and rats of 300 and 500 mg/kg, respectively. Clinical signs consisted of marked sensitivity to touch and disturbance, rapid breathing, and brown perinasal staining in rats administered 500 mg/kg. In mice, tremors, sensitivity to touch, eyes partly closed, and hypoactivity were seen after 200 and 300 mg/kg, as well as rapid, noisy and/or labored breathing, incoordination, unsteady gait, leaning, salivation, and hyperactivity after 400 and 500 mg/kg. When administered as two vortioxetine doses given an hour apart (200 mg/kg), clinical signs included convulsions, and resulted in death. Carcinogenicity studies were conducted in which mice and 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 2 years. In rats, the incidence of benign polypoid adenomas of the rectum was statistically significantly increased in females. 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. In mice, vortioxetine was not carcinogenic in males or females. Vortioxetine caused developmental delays when administered during pregnancy to rats and rabbits. Developmental delays were also seen after birth in rats treated with vortioxetine during pregnancy and through lactation. There were no teratogenic effects in rats or rabbits treated with the drug during organogenesis. Treatment of rats with vortioxetine at doses up to 120 mg/kg/day had no effect on male or female fertility. Vortioxetine was not genotoxic in the in vitro bacterial reverse mutation assay (Ames test) and in the in vivo rat bone marrow micronucleus assay.

Liver test abnormalities occur in a small proportion of patients (

Potentially serious, sometimes fatal adverse reactions may occur in patients who are receiving or have recently received a monoamine oxidase (MAO) inhibitor and then initiate therapy with serotonergic antidepressants or in those who received SSRI or SNRI therapy shortly before initiation of an MAO inhibitor. Concomitant use of MAO inhibitors intended to treat psychiatric disorders with vortioxetine is contraindicated. In addition, at least 2 weeks should elapse between discontinuance of an MAO inhibitor intended to treat psychiatric disorders and initiation of vortioxetine and at least 3 weeks should elapse between discontinuance of vortioxetine and initiation of an MAO inhibitor intended to treat psychiatric disorders.|Concomitant use of vortioxetine and a selective serotonin-reuptake inhibitor (SSRI) or selective serotonin- and norepinephrine-reuptake inhibitor (SNRI) is associated with a risk of serious, sometimes fatal, serotonin syndrome. If concomitant use of vortioxetine and an SSRI or SNRI is clinically warranted, patients should be advised of the increased risk for serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome manifestations occur, treatment with vortioxetine and the concurrently administered SSRI or SNRI should be discontinued immediately and supportive and symptomatic treatment should be initiated.|Concomitant use of vortioxetine and diuretics may increase the risk of hyponatremia.|When vortioxetine is administered concurrently with carbamazepine (a potent CYP inducer) for longer than 14 days, increasing the dosage of vortioxetine should be considered. The manufacturer recommends that the maximum dosage of vortioxetine not exceed 3 times the original dosage. Following discontinuance of carbamazepine, the original vortioxetine dosage should be resumed within 14 days.|For more Interactions (Complete) data for VORTIOXETINE (26 total), please visit the HSDB record page.

As with selective serotonin-reuptake inhibitors (SSRIs) and other newer antidepressants, Trintellix may cause mydriasis and should be used with caution in patients with raised intraocular pressure or those with narrow angle glaucoma.|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. 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. Brintellix has not been evaluated for use in pediatric patients.|Symptoms of mania and hypomania have been reported in less than 0.1% of patients receiving vortioxetine in clinical studies. Activation of mania and hypomania also have been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. Vortioxetine should therefore be used with caution in patients with a personal or family history of bipolar disorder, mania, or hypomania.|Seizures are a potential risk with antidepressant drugs. During short-term clinical trials in patients with Major Depressive Disorder and no history of seizure disorders, seizures were reported in <0.1% of patients that received Trintellix compared to 0% that received placebo. As with other antidepressants, Trintellix should be introduced cautiously in patients who have a history of seizures or in patients with unstable epilepsy. Treatment should be discontinued in any patient who develops seizures or for whom there is an increase in seizure frequency.|Epidemiological studies show an increased risk of bone fractures following exposure to some antidepressants, including selective serotonin-reuptake inhibitors (SSRIs) and other newer antidepressants. The risks appear to be greater at the initial stages of treatment, but significant increased risks were also observed at later stages of treatment. The possibility of fracture should be considered in the care of patients treated with Trintellix. Elderly patients and patients with important risk factors for bone fractures should be advised of possible adverse events which increase the risk of falls, such as dizziness and orthostatic hypotension, especially at the early stages of treatment but also soon after withdrawal. Preliminary data from observational studies show association of SSRIs/serotonin- and norepinephrine-reuptake inhibitors (SNRIs) and low bone mineral density in older men and women. Until further information becomes available, a possible effect on bone mineral density with long term treatment with SSRIs and other newer antidepressants including Trintellix, cannot be excluded, and may be a potential concern for patients with osteoporosis or major risk factors for bone fractures.

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 renal (mild, moderate, severe, ESRD) impairment is observed.

Vortioxetine is indicated for the treatment of major depressive disorder (MDD).|FDA Label|Treatment of major depressive episodes in adults.|Treatment of major depressive disorder

Vortioxetine is a serotonergic antidepressant used for major depression disorders. Vortioxetine has been associated with a low rate of minor serum aminotransferase elevations during treatment, but has not been linked to instances of clinically apparent acute liver injury.

Antidepressant Agents

Anti-Anxiety Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT3 Receptor Antagonists; Serotonin Uptake Inhibitors|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health(NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Vortioxetine is included in the database.|Brintellix is indicated for the treatment of major depressive disorder (MDD). The efficacy of Brintellix was established in six 6 to 8 week studies (including one study in the elderly) and one maintenance study in adults. /Included in US product label/

/BOX WARNING/ 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. 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. Brintellix has not been evaluated for use in pediatric patients.|Potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants, including vortioxetine, when used alone, but particularly with concurrent use of other serotonergic drugs (including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists ("triptans"), tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort (Hypericum perforatum)) and with drugs that impair the metabolism of serotonin (particularly monoamine oxidase (MAO) inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue). Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, 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 GI symptoms (e.g., nausea, vomiting, diarrhea). Patients receiving vortioxetine should be monitored for the development of serotonin syndrome. Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated. Use of an MAO inhibitor intended to treat psychiatric disorders within 3 weeks of vortioxetine discontinuance also is contraindicated. Vortioxetine also should not be initiated in patients who are being treated with other MAO inhibitors such as linezolid or IV methylene blue. If concurrent therapy with vortioxetine and other serotonergic drugs is clinically warranted, the patient should be made aware of the potential increased risk for serotonin syndrome, particularly during initiation of therapy or when dosage is increased. If manifestations of serotonin syndrome occur, treatment with vortioxetine and any concurrently administered serotonergic agents should be immediately discontinued and supportive and symptomatic treatment initiated.|Serotonergic antidepressants, including vortioxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiologic studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. The manufacturer recommends that patients be advised of the increased risk of bleeding associated with concomitant use of vortioxetine and aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation or bleeding.|Treatment with serotonergic drugs, including vortioxetine, may result in hyponatremia. In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case of hyponatremia with a serum sodium concentration lower than 110 mmol/L has been reported with vortioxetine in a premarketing study. Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia with serotonergic antidepressants. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death. Vortioxetine should be discontinued and appropriate medical intervention should be instituted in patients with symptomatic hyponatremia.|For more Drug Warnings (Complete) data for VORTIOXETINE (18 total), please visit the HSDB record page.

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 by inhibition of the serotonin transporter (IC50=5.4 nM). Specifically, vortioxetine binds to 5­HT3 (Ki=3.7 nM), 5­HT1A (Ki=15 nM), 5­HT7 (Ki=19 nM), 5­HT1D (Ki=54 nM), and 5­HT1B (Ki=33 nM), receptors and is a 5­HT3, 5­HT1D, and 5­HT7 receptor antagonist, 5­HT1B receptor partial agonist, and 5­HT1A receptor agonist.

Agents that alleviate ANXIETY, tension, and ANXIETY DISORDERS, promote sedation, and have a calming effect without affecting clarity of consciousness or neurologic conditions. ADRENERGIC BETA-ANTAGONISTS are commonly used in the symptomatic treatment of anxiety but are not included here. (See all compounds classified as Anti-Anxiety Agents.)|Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems. (See all compounds classified as Antidepressive Agents.)|Endogenous compounds and drugs that specifically stimulate SEROTONIN 5-HT1 RECEPTORS. Included under this heading are agonists for one or more of the specific 5-HT1 receptor subtypes. (See all compounds classified as Serotonin 5-HT1 Receptor Agonists.)|Drugs that bind to but do not activate SEROTONIN 5-HT3 RECEPTORS, thereby blocking the actions of SEROTONIN or SEROTONIN 5-HT3 RECEPTOR AGONISTS. (See all compounds classified as Serotonin 5-HT3 Receptor Antagonists.)|Compounds that specifically inhibit the reuptake of serotonin in the brain. (See all compounds classified as Serotonin Uptake Inhibitors.)

The maximal plasma vortioxetine concentration (Cmax) after dosing is reached within 7 to 11 hours postdose. Absolute bioavailability is 75%. No effect of food on the pharmacokinetics was observed.|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 apparent volume of distribution of vortioxetine is approximately 2600 L, indicating extensive extravascular distribution.|/MILK/ It is not known whether vortioxetine is present in human milk. Vortioxetine is present in the milk of lactating rats.|Vortioxetine is a new multi-modal drug against major depressive disorder with high affinity for a range of different serotonergic targets in the CNS. We report the (11)C-labeling of vortioxetine with (11)C-MeI using a Suzuki-protocol that allows for the presence of an unprotected amine. Preliminary evaluation of (11)C-vortioxetine in a Danish Landrace pig showed rapid brain uptake and brain distribution in accordance with the pharmacological profile, all though an unexpected high binding in cerebellum was also observed. (11)C-vortioxetine displayed slow tracer kinetics with peak uptake after 60 min and with limited wash-out from the brain. Further studies are needed but this radioligand may prove to be a valuable tool in unraveling the clinical effects of vortioxetine.|Vortioxetine and related material was mainly excreted by faeces in mice (84%), rats (69%) and dogs (59-65% in two separate studies), whereas humans showed prominent urinary excretion (59%) compared to faeces (26%). In excretion studies, the recovery of (14)C-Vortioxetine and related material was close to 100% in rodents. Dogs and humans exhibited a protracted excretion and the recovery was approximately 90% and 85% after 168 hours and 360 hours, respectively.|The objective was to describe the pharmacokinetics of vortioxetine and evaluate the effect of intrinsic and extrinsic factors in the healthy population. Data from 26 clinical pharmacology studies were pooled. A total of 21,758 vortioxetine quantifiable plasma concentrations were collected from 887 subjects with corresponding demography. The doses ranged from 2.5 to 75 mg (single dose) and 2.5-60 mg (multiple QD doses). The pharmacokinetics of vortioxetine was best characterised by a two-compartment model with first-order absorption, lag-time and linear elimination, with interindividual error terms for absorption rate constant, oral clearance and central volume of distribution. The population mean was 32.7 L/hr for oral clearance and 1.97*10(3) L for the central volume of distribution. The average elimination half-life was 65.8 hr. CYP2D6 inferred metabolic status (ultra, extensive, intermediate or poor metabolisers) and age on oral clearance and height on central volume of distribution were identified as statistically significant covariate-parameter relationships. For CYP2D6 poor metabolizers, CL/F was approximately 50% to that seen in CYP2D6 extensive metabolizers. The impact of height on V2/F and age on CL/F was low and not considered to be clinically relevant. The final model was found to be reliable, stable and predictive. A reliable, stable and predictive pharmacokinetic model was developed to characterize pharmacokinetics of vortioxetine in the healthy population.|For more Absorption, Distribution and Excretion (Complete) data for VORTIOXETINE (10 total), please visit the HSDB record page.

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.|All metabolites detected in human hepatocytes were also present in dogs, mice and rats (plasma and/or urine) in vivo, except for a glucuronide conjugate of monohydroxy-Vortioxetine which was not found in mice or rats. Among all species tested, rabbit hepatocytes appeared to have the metabolite profile closer to human hepatocyte metabolite profile.

Mean terminal half­life is approximately 66 hours|The oral absolute bioavailability was approximately 10% in the rat, 48% in the dog and 75% in patients, with terminal elimination half-life values of 3.0, 7.9 and 66 hours, respectively.|... Data from 26 clinical pharmacology studies were pooled. A total of 21,758 vortioxetine quantifiable plasma concentrations were collected from 887 subjects with corresponding demography. The doses ranged from 2.5 to 75 mg (single dose) and 2.5-60 mg (multiple QD doses). ... The average elimination half-life was 65.8 hr. ...|The mean elimination half-life and oral clearance are 66 hours and 33 L/hr, respectively.

Vortioxetine is classified as a serotonin modulator and simulator (SMS) as it has a multimodal mechanism of action towards the serotonin neurotransmitter system whereby it simultaneously modulates one or more serotonin receptors and inhibits the reuptake of serotonin. More specifically, vortioxetine acts via the following biological mechanisms: as a serotonin reuptake inhibitor (SRI) through inhibition of the serotonin transporter, while also acting as a partial agonist of the 5-HT1B receptor, an agonist of 5-HT1A, and antagonist of the 5-HT3, 5-HT1D, and 5-HT7 receptors.|1-(2-(2,4-Dimethylphenyl-sulfanyl)-phenyl)-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K(i) = 3.7 nM), h5-HT(7) receptor antagonist (K(i) = 19 nM), h5-HT(1B) receptor partial agonist (K(i) = 33 nM), h5-HT(1A) receptor agonist (K(i) = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K(i) = 1.6 nM) (J Med Chem 54:3206-3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT(1B) receptor agonist [EC(50) = 460 nM, intrinsic activity = 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT(7) receptor antagonist (K(i) = 200 nM and IC(50) = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT(1B) receptor and rSERT (ED(50) = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT(3) receptor antagonist in the Bezold-Jarisch reflex assay (ED(50) = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT(3) receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant- and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.|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.|The monoaminergic network, including serotonin (5-HT), norepinephrine (NE), and dopamine (DA) pathways, is highly interconnected and has a well-established role in mood disorders. Preclinical research suggests that 5-HT receptor subtypes, including 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors as well as the 5-HT transporter (SERT), may have important roles in treating depression. This study evaluated the neuropharmacological profile of Lu AA21004, a novel multimodal antidepressant combining 5-HT3 and 5-HT7 receptor antagonism, 5-HT1B receptor partial agonism, 5-HT1A receptor agonism, and SERT inhibition in recombinant cell lines. Extracellular 5-HT, NE and DA levels were evaluated in the ventral hippocampus (vHC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute and subchronic treatment with Lu AA21004 or escitalopram. The acute effects of LuAA21004 on NE and DA neuronal firing were also evaluated in the locus coeruleus (LC) and ventral tegmental area (VTA), respectively. Acute Lu AA21004 dose-dependently increased 5-HT in the vHC, mPFC and NAc. Maximal 5-HT levels in the vHC were higher than those in the mPFC. Furthermore, mPFC 5-HT levels were increased at low SERT occupancy levels. In the vHC and mPFC, but not the NAc, high Lu AA21004 doses increased NE and DA levels. Lu AA21004 slightly decreased LC NE neuronal firing and had no effect on VTA DA firing. Results are discussed in context of occupancy at 5-HT3, 5-HT1B and 5-HT1A receptors and SERT. In conclusion, Lu AA21004, acting via two pharmacological modalities, 5-HT receptor modulation and SERT inhibition, results in a brain region-dependent increase of multiple neurotransmitter concentrations. and ECNP. All rights reserved. PMID:22612991|Vortioxetine, a novel antidepressant with multimodal action, is a serotonin (5-HT)3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist and a 5-HT transporter (SERT) inhibitor. Vortioxetine has been shown to improve cognitive performance in several preclinical rat models and in patients with major depressive disorder. Here we investigated the mechanistic basis for these effects by studying the effect of vortioxetine on synaptic transmission, long-term potentiation (LTP), a cellular correlate of learning and memory, and theta oscillations in the rat hippocampus and frontal cortex. Vortioxetine was found to prevent the 5-HT-induced increase in inhibitory post-synaptic potentials recorded from CA1 pyramidal cells, most likely by 5-HT3 receptor antagonism. Vortioxetine also enhanced LTP in the CA1 region of the hippocampus. Finally, vortioxetine increased fronto-cortical theta power during active wake in whole animal electroencephalographic recordings. In comparison, the selective SERT inhibitor escitalopram showed no effect on any of these measures. Taken together, our results indicate that vortioxetine can increase pyramidal cell output, which leads to enhanced synaptic plasticity in the hippocampus. Given the central role of the hippocampus in cognition, these findings may provide a cellular correlate to the observed preclinical and clinical cognition-enhancing effects of vortioxetine.|For more Mechanism of Action (Complete) data for VORTIOXETINE (7 total), please visit the HSDB record page.

No specific antidotes for Brintellix are known. In managing over dosage, consider the possibility of multiple drug involvement.

/SIGNS AND SYMPTOMS/ There is limited clinical trial experience regarding human overdosage with Brintellix. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of Brintellix. The maximum single dose tested was 75 mg in men. Ingestion of Brintellix 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.|/SIGNS AND SYMPTOMS/ Potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants, including vortioxetine, when used alone, but particularly with concurrent use of other serotonergic drugs (including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists ("triptans"), tricyclic antidepressants, buspirone, fentanyl, lithium, tramadol, tryptophan, and St. John's wort (Hypericum perforatum)) and with drugs that impair the metabolism of serotonin (particularly monoamine oxidase (MAO) inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue). Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, 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 GI symptoms (e.g., nausea, vomiting, diarrhea). Patients receiving vortioxetine should be monitored for the development of serotonin syndrome. Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated. Use of an MAO inhibitor intended to treat psychiatric disorders within 3 weeks of vortioxetine discontinuance also is contraindicated. Vortioxetine also should not be initiated in patients who are being treated with other MAO inhibitors such as linezolid or IV methylene blue. If concurrent therapy with vortioxetine and other serotonergic drugs is clinically warranted, the patient should be made aware of the potential increased risk for serotonin syndrome, particularly during initiation of therapy or when dosage is increased. If manifestations of serotonin syndrome occur, treatment with vortioxetine and any concurrently administered serotonergic agents should be immediately discontinued and supportive and symptomatic treatment initiated.|/SIGNS AND SYMPTOMS/ 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. 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. Brintellix has not been evaluated for use in pediatric patients.|/SIGNS AND SYMPTOMS/ Treatment with serotonergic drugs, including vortioxetine, may result in hyponatremia. In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case of hyponatremia with a serum sodium concentration lower than 110 mmol/L has been reported with vortioxetine in a premarketing study. Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia with serotonergic antidepressants. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death. Vortioxetine should be discontinued and appropriate medical intervention should be instituted in patients with symptomatic hyponatremia.|/GENOTOXICITY/ Vortioxetine was not genotoxic in ... an in vitro chromosome aberration assay in cultured human lymphocytes ... .

1-(2-(2,4-dimethylphenylsulfanyl)phenyl)piperazine

Oral: 5 mg, 10 mg, and 20 mg tablets, Trintellix /Vortioxetine hydrobromide/|Table: Vortioxetine Hydrobromide Preparations [Table#8242]

In this work, a simple, sensitive and fast ultra performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitative determination of vortioxetine in rat plasma. Plasma samples were processed with a protein precipitation. The separation was achieved by an Acquity UPLC BEH C18 column (2.1mmx50mm, 1.7um) column with a gradient mobile phase consisting of 0.1% formic acid in water and acetonitrile. Detection was carried out using positive-ion electrospray tandem mass spectrometry via multiple reaction monitoring (MRM). The validated method had an excellent linearity in the range of 0.05-20ng/mL (R2>0.997) with a lower limit of quantification (0.05ng/mL). The extraction recovery was in the range of 78.3-88.4% for vortioxetine and 80.3% for carbamazepine (internal standard, IS). The intra- and inter-day precision was below 8.5% and accuracy was from -11.2% to 9.5%. No notable matrix effect and astaticism was observed for vortioxetine. The method has been successfully applied to a pharmacokinetic study of vortioxetine in rats for the first time, which provides the basis for the further development and application of vortioxetine.

Human drugs -> Brintellix -> EMA Drug Category|Psychoanaleptics -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients