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Laboratory Tests Trintellix has not been associated with any clinically important changes in laboratory test parameters in serum chemistry except sodium , hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies. Hyponatremia has been reported with the treatment of Trintellix [see Warnings and Precautions 5. In the six month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Trintellix during the initial 12 week, open-label phase, there were no clinically important changes in lab test parameters between Trintellix and placebo-treated patients.
Weight Trintellix had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies.
In the six month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Trintellix during the initial 12 week, open-label phase, there was no significant effect on body weight between Trintellix and placebo-treated patients. Vital Signs Trintellix has not been associated with any clinically significant effects on vital signs, including systolic and diastolic blood pressure and heart rate, as measured in placebo-controlled studies.
Other Adverse Reactions Observed in Clinical Studies The following listing does not include reactions: 1 already listed in previous tables or elsewhere in labeling, 2 for which a drug cause was remote, 3 which were so general as to be uninformative, 4 which were not considered to have significant clinical implications, or 5 which occurred at a rate equal to or less than placebo.
Ear and labyrinth disorders — vertigo Gastrointestinal disorders — dyspepsia Vascular disorders — flushing Postmarketing Experience The following adverse reactions have been identified during postapproval use of Trintellix. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serotonergic Drugs Based on the mechanism of action of Trintellix and the potential for serotonin toxicity, serotonin syndrome may occur when Trintellix is coadministered with other drugs that may affect the serotonergic neurotransmitter systems e. Closely monitor symptoms of serotonin syndrome if Trintellix is coadministered with other serotonergic drugs. Treatment with Trintellix and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs [see Warnings and Precautions 5.
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. Details on the potential pharmacokinetic interactions between Trintellix and bupropion can be found in Section 7.
Drugs That Interfere with Hemostasis e. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.
These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when Trintellix is initiated or discontinued [see Warnings and Precautions 5.
Consider increasing the Trintellix dose when a strong CYP inducer e. The maximum dose is not recommended to exceed three times the original dose [see Dosage and Administration 2. Figure 1. In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary. Chronic administration of Trintellix is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms.
Furthermore, in a series of clinical drug interaction studies, coadministration of Trintellix with substrates for CYP2B6 e. Because vortioxetine is highly bound to plasma protein, coadministration of Trintellix with another drug that is highly protein bound may increase free concentrations of the other drug.
Figure 2. No malformations were seen at doses up to 77 times and 58 times the MRHD, respectively. 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. 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. Monitor neonates who were exposed to Trintellix in the third trimester of pregnancy for PPHN and drug discontinuation syndrome [see Data ]. These findings are based on postmarketing reports.
Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying.
In some cases, the clinical picture was consistent with serotonin syndrome [see Warnings and Precautions 5. PPHN occurs in one to two per 1, live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of women whose infants were born with PPHN and women whose infants were born healthy, the risk for developing PPHN was approximately six fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy.
Lactation Risk Summary There is no information regarding the presence of vortioxetine in human milk, the effects on the breastfed infant, or the effects on milk production. Vortioxetine is present in rat milk [see Data ]. Milk to plasma ratio in lactating rats was 1, 1.
Pediatric Use Clinical studies on the use of Trintellix in pediatric patients have not been conducted; therefore, the safety and effectiveness of Trintellix in the pediatric population have not been established.
Geriatric Use No dose adjustment is recommended on the basis of age Figure 3. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions 5.
Use in Other Patient Populations No dose adjustment of Trintellix on the basis of race, gender, ethnicity, or renal function from mild renal impairment to end-stage renal disease is necessary. In addition, the same dose can be administered in patients with mild to severe hepatic impairment Figure 3 [see Clinical Pharmacology Figure 3.
Overdosage Human Experience There is limited clinical trial experience regarding human overdosage with Trintellix. In premarketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of Trintellix. The maximum single dose tested was 75 mg in men. Ingestion of Trintellix in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing.
There have been postmarketing reports of overdoses of Trintellix. The most frequently reported symptoms with overdoses up to 80 mg four times the maximum recommended daily dose were nausea and vomiting.
With overdoses greater than 80 mg, a case of serotonin syndrome in combination with another serotonergic drug, and a case of seizure, have been reported. Management of Overdose No specific antidotes for Trintellix are known. In managing overdosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at for latest recommendations. Vortioxetine HBr is known chemically as 1-[2- 2,4-Dimethyl-phenylsulfanyl -phenyl]-piperazine, hydrobromide.
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. 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 , iron oxide red 5 mg and 20 mg and iron oxide yellow 10 mg.
Trintellix - Clinical Pharmacology 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.
Effect on Cardiac Repolarization The effect of vortioxetine 10 mg and 40 mg administered once daily on QTc interval was evaluated in a randomized, double-blind, placebo-, and active-controlled moxifloxacin mg , four-treatment-arm parallel study in male subjects.
The oral dose of 40 mg is sufficient to assess the effect of metabolic inhibition. Pharmacokinetics Vortioxetine pharmacological activity is due to the parent drug. The pharmacokinetics of vortioxetine 2. The mean terminal half-life is approximately 66 hours, and steady-state plasma concentrations are typically achieved within two weeks of dosing. Absorption The maximal plasma vortioxetine concentration Cmax after dosing is reached within 7 to 11 hours postdose Tmax.
No effect of food on the pharmacokinetics was observed. Distribution The apparent volume of distribution of vortioxetine is approximately L, indicating extensive extravascular distribution. No apparent difference in the plasma protein binding between healthy subjects and subjects with hepatic mild, moderate or severe or renal mild, moderate, severe, ESRD impairment is observed.
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. Negligible amounts of unchanged vortioxetine were excreted in the urine up to 48 hours.
The presence of hepatic mild, moderate or severe or renal impairment mild, moderate, severe and ESRD did not affect the apparent clearance of vortioxetine. In rats, the incidence of benign polypoid adenomas of the rectum was statistically significantly increased in females at doses 39 times the MRHD, but not at 15 times the MRHD. These were considered related to inflammation and hyperplasia and possibly caused by an interaction with a vehicle component of the formulation used for the study.
The finding did not occur in male rats at 20 times the MRHD. In mice, vortioxetine was not carcinogenic in males or females at doses up to 12 and 24 times, respectively, the MRHD. Mutagenicity Vortioxetine was not genotoxic in the in vitro bacterial reverse mutation assay Ames test , an in vitro chromosome aberration assay in cultured human lymphocytes, and an in vivo rat bone marrow micronucleus assay. Adults aged 18 years to 75 years The efficacy of Trintellix in patients aged 18 years to 75 years was demonstrated in five, 6 to 8 week, placebo-controlled studies Studies 1 to 5 in Table 4.
In these studies, patients were randomized to Trintellix 5 mg, 10 mg, 15 mg or 20 mg or placebo once daily. In each of these studies, at least one dose group of Trintellix was superior to placebo in improvement of depressive symptoms as measured by mean change from baseline to endpoint visit on the primary efficacy measurement see Table 4.
Subgroup analysis by age, gender or race did not suggest any clear evidence of differential responsiveness. Two studies of the 5 mg dose in the U. Elderly Study aged 64 years to 88 years The efficacy of Trintellix for the treatment of MDD was also demonstrated in a randomized, double-blind, placebo-controlled, fixed-dose study of Trintellix in elderly patients aged 64 years to 88 years with MDD Study 6 in Table 4.
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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. Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients daily. If concomitant use of TRINTELLIX is clinically warranted, patients should be made aware of and monitored for potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Prior to initiating treatment with an antidepressant, screen patients for bipolar disorder.
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Laboratory Tests Trintellix has not been associated with any clinically important changes in laboratory test parameters in serum chemistry except sodium , hematology and urinalysis as measured in the 6 to 8 week placebo-controlled studies. Hyponatremia has been reported with the treatment of Trintellix [see Warnings and Precautions 5. In the six month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Trintellix during the initial 12 week, open-label phase, there were no clinically important changes in lab test parameters between Trintellix and placebo-treated patients. Weight Trintellix had no significant effect on body weight as measured by the mean change from baseline in the 6 to 8 week placebo-controlled studies. In the six month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Trintellix during the initial 12 week, open-label phase, there was no significant effect on body weight between Trintellix and placebo-treated patients.