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

Contraindications

Hypersensitivity

Coadministration with MAOIs

• Coadministration of MAOIs with vortioxetine or within 3 weeks of discontinuing vortioxetine
• Initiating vortioxetine within 14 days of stopping an MAOI
• Starting vortioxetine in a patient who is being treated with linezolid or IV methylene blue is contraindicated because of an increased risk of serotonin syndrome
• If linezolid or IV methylene blue must be administered, discontinue vortioxetine immediately and monitor for CNS toxicity; monitor for symptoms of serotonin syndrome for 3 weeks or until 24 hours after the last dose of linezolid or methylene blue; may resume vortioxetine 24 hr after last dose of linezolid or methylene blue

Cautions

Clinical worsening of depression and suicide risk (see Black Box Warning)

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

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 (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort); if symptoms occur, discontinue therapy and initiate supportive treatment; if concomitant use with other serotonergic drugs is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases

Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase risk of abnormal bleeding. patients should be cautioned about increased risk of bleeding when vortioxetine is coadministered with nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation

Increases risk of hyponatremia and cognitive impairment especially in the elderly or volume depleted patients; hyponatremia can occur in association with the syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Angioedema reported with use

Seizures reported; use caution in patients with history of seizure disorders or conditions predisposing to seizures

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

Bone fractures reported with antidepressant treatment; consider possibility of fracture if antidepressant-treated patient presents with unexplained bone pain

Use not recommended in severe hepatic impairment

Discontinuation syndrome may occur with abrupt discontinuation; symptoms may include nausea, vomiting, diminished appetite, tremors, chills diarrhea, headaches, lightheadedness, fatigue, sleep disturbances (ie, insomnia, vivid dreams), and somnolence

Pregnancy

A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy; the women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants; consider risks of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum

Exposure to serotonergic antidepressants 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 therapy 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; vortioxetine is present in rat milk; developmental and health benefits of breastfeeding should be considered 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: 9, 18, and 33 ng/mL following doses of 5, 10, and 20 mg/day

Peak plasma time: 7-11 hr

Distribution

Protein bound: 98%

Vd: 2600 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

May take with or without food

Discontinuation

• Can be abruptly discontinued, although patients may experience transient adverse reactions (eg, headache, muscle tension) if dose is 15-20 mg/day
• To avoid these adverse reactions, decreased dose to 10 mg/day for 1 week before full