vortioxetine (Rx)

>10%

Nausea (21-32%)

1-10%

Diarrhea (7-10%)

Dizziness (6-9%)

Dry mouth (6-8%)

Constipation (3-6%)

Vomiting (3-6%)

Flatulence (1-3%)

Pruritus (1-3%)

Abnormal dreams (<1-3%)

Postmarketing Reports

Weight gain

Acute pancreatitis

Angle closure glaucoma

Seizure

Rash, generalized rash

Difficulties in sexual desire, sexual performance, and sexual satisfaction

Aggression, agitation, anger, hostility, irritability

Contraindications

Hypersensitivity to vortioxetine or any component of formulation

MAOI

• Use of MAOIs (intended to treat psychiatric disorders) or within 21 days of discontinuing with vortioxetine
• Use of vortioxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders
• Currently being treated with another MAOI (eg, linezolid, IV methylene blue)

Cautions

May worsen mania symptoms or activate mania/hypomania in patients with bipolar disorder

Risk of mydriasis; may trigger angle closure attack in patients with angle-closure glaucoma with anatomically narrow angles without a patent iridectomy

Increases risk of hyponatremia and cognitive impairment especially in the elderly; hyponatremia can occur in association with the syndrome of inappropriate antidiuretic hormone secretion (SIADH); patients taking diuretics or who are otherwise volume-depleted can be at greater risk; consider discontinuation of drug in patients with symptomatic hyponatremia; appropriate medical intervention should be instituted

Dosage reduction is recommended in patients known to be poor CYP2D6 metabolizers because these patients have higher vortioxetine plasma concentrations than extensive CYP2D6 metabolizers

Suicidal thoughts and behaviors in adolescents and young adults

• In pooled studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (<24 years) taking antidepressants for MDD and other psychiatric illnesses
• Variations in risk of suicidal thoughts and behaviors among drugs and across the different indications, highest incidence in patients with MDD
• Unknown if risk extends to longer-term use
• Closely monitor for behavioral changes, clinical worsening, and suicidal tendencies during initial 1-2 months of therapy and dosage adjustments
• Counsel family members or caregivers to monitor for changes in behavior and to alert the healthcare provider; consider changing the therapeutic regimen, including possibly discontinuing therapy, in patients whose depression is persistently worse, or who are experiencing emergent of suicidal thoughts and behaviors

Serotonin syndrome

• Serotonin syndrome reported with serotonergic antidepressants (SSRIs, SNRIs, and others), including with vortioxetine, both when taken alone, but especially when coadministered with other serotonergic agents (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, St. John's Wort)
• Symptoms include mental status changes, autonomic instability, neuromuscular symptoms, seizures, and/or gastrointestinal symptoms
• If symptoms occur, discontinue therapy and initiate supportive treatment
• If concomitant use with other serotonergic drugs is clinically warranted, advise of potential risks for serotonin syndrome, particularly during treatment initiation and dose increases

Discontinuation syndrome

• Adverse reactions reported upon abrupt discontinuation of treatment at doses of 15-20 mg/day
• Gradual reduction in dosage 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, tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures

Drug interaction overview

• Substrate of CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6

• Increase of serotonin syndrome

  • Contraindicated with MAOIs
  • Coadministration with serotonergic drugs increases the risk of serotonin syndrome
  • Monitor; if serotonin syndrome occurs, consider discontinuing vortioxetine

• Strong CYP2D6 inhibitor

  • Coadministration with strong CYP2D6 inhibitors increases plasma concentrations of vortioxetine

• Strong CYP inducers

  • Coadministration with strong CYP2D6 inhibitors decreases plasma concentrations of vortioxetine

• Drugs that interfere coagulation or bleeding

  • Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase risk of abnormal bleeding
  • Exercise caution with concomitant use of vortioxetine with nonsteroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents, anticoagulants, or other drugs that affect coagulation
  • Monitor INR when used with warfarin

• Drugs highly bound to plasma protein

  • Coadministration of vortioxetine with drugs highly bound to plasma protein (eg, warfarin) may increase free concentrations of vortioxetine or other highly bound drugs in plasma
  • Monitor for adverse reactions and reduce dosage of both protein bound drugs as needed

Pregnancy

Limited human data available on use during pregnancy to inform any drug-associated risks

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy; healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1- 844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research- programs/pregnancyregistry/antidepressants/

Animal data

• Administered to pregnant rats and rabbits during organogenesis at doses ≥15 times and 10x the maximum recommended human dose (MRHD), respectively, resulted in decreased fetal body weight and delayed ossification
• No malformations were seen at doses up to 77x and 58x the MRHD, respectively
• Orally administered to pregnant rats during gestation and lactation at doses ≥20x the MRHD resulted in a decrease in the number of live-born pups and an increase in early postnatal pup mortality
• Decreased pup weight at birth to weaning occurred at 58x the MRHD and delayed physical development occurred at ≥20 times the MRHD
• Advise pregnant females of the potential risk to a fetus

Clinical consideration

• 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
• Exposure to serotonergic antidepressants, including vortioxetine, in late pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN); monitor neonates who were exposed to drug in the third trimester of pregnancy for PPHN and drug discontinuation syndrome

Lactation

There is no information regarding presence of vortioxetine in human milk, effects on the breastfed infant, or effects on milk production

Present in rat milk

Consider developmental and health benefits of breastfeeding along with mother's clinical need for therapy and any potential adverse effects on breastfed child from therapy or from underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

The mechanism of the antidepressant effect 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 the antidepressant effect has not been established

Absorption

Peak plasma concentration at steady-state: 9 ng/mL (5 mg/day), 18ng/mL (10 mg/day), 33 ng/mL (20 mg/day)

Peak plasma time: 7-11 hr

Absolute bioavailability: 75%

Distribution

Protein bound: 98%

Vd: 2,600 L (extensive extravascular distribution)

Metabolism

Extensively metabolized primarily through oxidation via CYP450 isozymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6 and subsequent glucuronic acid conjugation

CYP2D6 is the primary metabolic pathway

Metabolites: Carboxylic acid metabolite (inactive)

Elimination

Half-life: 66 hr

Excretion: 59% urine; 26% feces

Pharmacogenomics

Poor metabolizers of CYP2D6 have ~twice the vortioxetine plasma concentration of extensive metabolizers

Oral Administration

Take with or without food

Storage

Store at 77ºF (25ºC); excursions permitted to 59-86ºF (15-30ºC)