Vortioxetine Hydrobromide

Contraindications

• Known hypersensitivity to vortioxetine or any ingredients in the formulation.1 Angioedema reported in vortioxetine-treated patients.1

• Concurrent or recent (i.e., within 2 weeks) therapy with an MAO inhibitor intended to treat psychiatric disorders.1 Use of an MAO inhibitor intended to treat psychiatric disorders within 3 weeks of vortioxetine discontinuance.1 (See Serotonin Syndrome under Cautions and also see Specific Drugs under Interactions.)

• Initiation of vortioxetine in patients receiving MAO inhibitors such as linezolid or IV methylene blue.1 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Possible worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs.1 28 43 44 45 (See Boxed Warning and also see Pediatric Use under Cautions.) However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1 43 44 45

Appropriately monitor and closely observe patients receiving vortioxetine for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 43 44 45

Anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania may be precursors to emerging suicidality.1 44 45 Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if severe, abrupt in onset, or were not part of the patient’s presenting symptoms.1 44

Other Warnings and Precautions

Potentially life-threatening serotonin syndrome reported with serotonergic antidepressants, including vortioxetine, when used alone, but particularly during concurrent therapy with other serotonergic drugs (e.g., 5-HT1 receptor agonists [triptans], TCAs, buspirone, fentanyl, lithium, tramadol, tryptophan, St. John’s wort [Hypericum perforatum]) and with drugs that impair the metabolism of serotonin (particularly MAO inhibitors, both those used to treat psychiatric disorders and others, such as linezolid and methylene blue).1 47 48 (See Contraindications under Cautions and also see Interactions.)

Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1 47 48

Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat psychiatric disorders is contraindicated.1 Use of an MAO inhibitor intended to treat psychiatric disorders within 3 weeks of vortioxetine discontinuance also contraindicated.1 Do not initiate vortioxetine in patients treated with other MAO inhibitors such as linezolid or IV methylene blue.1 (See Specific Drugs under Interactions.)

If concurrent therapy with other serotonergic drugs is clinically warranted, advise patient of potentially increased risk for serotonin syndrome, particularly during initiation of therapy and dosage increases.1

Monitor patients receiving vortioxetine for the development of serotonin syndrome.1 If manifestations occur, immediately discontinue vortioxetine and any concurrently administered serotonergic agents and initiate supportive and symptomatic treatment.1

Possible increased risk of bleeding with serotonergic antidepressants, including vortioxetine; events ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1 Concurrent use of aspirin, NSAIAs, warfarin, or other anticoagulants may increase risk.1 (See Specific Drugs under Interactions and also see Advice to Patients.)

Possible activation of mania and hypomania; use with caution in patients with personal or family history of bipolar disorder, mania, or hypomania.1

Pupillary dilation (mydriasis) occurs with many antidepressants, including vortioxetine, and may trigger an acute attack of angle-closure glaucoma (narrow-angle glaucoma) in patients with anatomically narrow angles who do not have a patent iridectomy.1 (See Advice to Patients.)

Treatment with serotonergic drugs, including vortioxetine, may result in hyponatremia; in many cases, SIADH is apparent cause.1 Increased risk in patients who are volume-depleted, elderly, or taking diuretics.1 Initiate appropriate medical intervention and consider drug discontinuance in patients with symptomatic hyponatremia.1

Ensure accuracy of prescription; similarity in spelling and pronunciation of Brintellix (former trade name of vortioxetine; changed to Trintellix in May 2016) and Brilinta (ticagrelor, a platelet-aggregation inhibitor) may result in medication errors.49 50 51 52

Specific Populations

Category C.1

Possible complications, sometimes severe and requiring prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care, in neonates exposed to SSRIs or SNRIs late in the third trimester; may arise immediately upon delivery.1 22 23 24 25 26 27

Consult joint APA and ACOG guidelines (at ) for additional information on management of depression in women prior to conception and during pregnancy, including treatment algorithms.35

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Safety and effectiveness not established in pediatric patients; not studied in such patients.1

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants).1 44 However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or ideation.28 No suicides occurred in these pediatric trials.1 28 44

Carefully consider these findings when assessing potential benefits and risks of vortioxetine in a child or adolescent for any clinical use.1 28 44 45 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

In clinical trials with vortioxetine, 11% of patients were ≥65 years of age, including those in a placebo-controlled study conducted specifically in geriatric patients.1 7 No overall differences in safety or effectiveness observed between geriatric and younger adults in these studies; other reported clinical experience has not identified any differences in response to vortioxetine between geriatric and younger adults.1 7 (See Geriatric Patients under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Serotonergic antidepressants, including vortioxetine, associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect.1 (See Hyponatremia/SIADH under Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults ≥65 years of age with antidepressant therapy compared with placebo.1 43 44 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.)

No dosage adjustment required in patients with mild or moderate hepatic impairment.1 Not studied in patients with severe hepatic impairment; use not recommended in such patients.1

No dosage adjustment is necessary in patients with mild, moderate, or severe renal impairment or end-stage renal disease.1 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Nausea,1 2 3 4 7 9 10 constipation,1 vomiting.1 2 Nausea is the most common adverse effect and occurs most often during the first week of treatment; incidence is dose related and higher in females than males.1 9 10

Absorption

Bioavailability

Absolute bioavailability of 75%.1 19

Peak plasma concentrations achieved within 7–11 hours after oral administration.1 19 Steady-state concentrations are achieved within 2 weeks.1

Onset

Antidepressant effect generally evident in 2 weeks; full antidepressant effect may take ≥4 weeks.1 2 3

Food

Administration with food does not affect pharmacokinetics.1 19 41

Distribution

Extent

Extensively distributed.1 19

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

98% (independent of plasma concentration).1 19

Elimination

Metabolism

Extensively metabolized via oxidation by CYP isoenzymes, principally by CYP2D6 with lesser contributions from CYP3A4/5, 2C19, 2C9, 2A6, 2C8, and 2B6, and subsequent glucuronic acid conjugation.1 11 19 20 CYP2D6 is the main enzyme catalyzing the metabolism of vortioxetine to its principal, inactive carboxylic acid metabolite.1

Elimination Route

59 and 26% recovered in the urine and feces, respectively, as metabolites.1 Negligible amounts of unchanged vortioxetine excreted in urine.1 19

Half-life

Approximately 66 hours.1

Special Populations

Mild or moderate hepatic impairment does not affect apparent clearance.1

Mild, moderate, or severe renal impairment or end-stage renal disease does not affect apparent clearance.1 Only a small fraction of a single, 10-mg dose of vortioxetine was removed by dialysis; AUC and peak plasma concentrations were 13 and 27% lower, respectively.41

In a single-dose pharmacokinetic study, pharmacokinetics generally similar between geriatric individuals >65 years of age and younger individuals (24–45 years of age).1

Poor CYP2D6 metabolizers: Plasma concentrations of vortioxetine are approximately twice those in extensive CYP2D6 metabolizers.1 (See Dosage under Dosage and Administration.)

Storage

Oral

25°C (may be exposed to 15–30°C).1

• Importance of providing copy of written patient information (medication guide) each time vortioxetine is dispensed.1 Importance of advising patients and their caregivers to read the patient information before taking vortioxetine and each time the prescription is refilled.1

• Importance of advising patients to check their prescription carefully to ensure that they have received the correct drug; prescribing and dispensing errors have been reported due to similarities in the spelling and pronunciation of Brintellix (the former trade name for vortioxetine, which was changed to Trintellix in May 2016) and Brilinta (the trade name for ticagrelor, a platelet aggregation inhibitor).49 50 51 (See Prescribing and Dispensing Precautions under Cautions.)

• Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.1 43 44 45 (See Worsening of Depression and Suicidality Risk under Cautions.)

• Importance of informing patients who are receiving vortioxetine 15 or 20 mg daily that they may experience possible withdrawal reactions (e.g., headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, runny nose) if they abruptly stop the drug.1 Patients should be advised not to stop taking vortioxetine without first talking with their clinician.1

• Importance of instructing patients not to take vortioxetine with or within 14 days of discontinuing an MAO inhibitor and to allow 21 days after stopping vortioxetine before starting an MAO inhibitor.1

• Importance of informing patients of potential risk of serotonin syndrome, particularly with concurrent use of vortioxetine and other serotonergic agents or antipsychotic agents.1 47 (See Interactions.) Importance of immediately contacting clinician if manifestations of serotonin syndrome develop (e.g., restlessness, hallucinations, delirium, loss of coordination, fast heart beat, increased body temperature, sweating, muscle stiffness, labile BP, diarrhea, coma, nausea, vomiting, confusion).1 47

• Importance of advising patients that vortioxetine can be taken with or without food, and should be taken at about the same time every day.1

• Importance of informing patients that if they receive diuretics, are otherwise volume depleted, or are elderly, that they may be at greater risk of developing hyponatremia while taking vortioxetine.1

• Importance of informing patients that nausea is the most common adverse effect associated with vortioxetine, and that it is dose related.1 Nausea commonly occurs within the first week of treatment then decreases in frequency, but can persist.1

• Risk of cognitive and motor impairment; although not observed in a trial in healthy individuals, importance of patients exercising caution while operating hazardous machinery, including driving a motor vehicle, until they are reasonably certain that vortioxetine therapy does not adversely affect their ability to engage in such activities.1

• Importance of advising patients to avoid alcohol consumption during vortioxetine therapy.1

• Importance of advising patients to notify their clinician if any signs or symptoms of an allergic reaction develop during therapy (e.g., rash, hives, swelling, difficulty breathing).1

• Importance of advising patients, their families, and caregivers to look for signs of activation of mania/hypomania.1

• Importance of advising patients that vortioxetine can cause mild pupillary dilation, which can lead to an episode of angle-closure glaucoma in susceptible individuals.1 Possible symptoms include eye pain, vision changes, and swelling or redness in or around the eye.1 Preexisting glaucoma is almost always open-angle glaucoma since angle-closure glaucoma can be treated definitively with iridectomy when diagnosed;1 open-angle glaucoma is not a risk factor for angle-closure glaucoma.1 Patients may wish to be examined to determine whether they are susceptible to angle-closure glaucoma and have a prophylactic procedure (e.g., iridectomy) if they are susceptible.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses (e.g., liver disease, glaucoma) or personal or family history of suicidality or bipolar disorder.1 Importance of advising patients about the risk of bleeding associated with concomitant use of vortioxetine with aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.