Vortioxetine

Vortioxetine is an atypical antipsychotic and antidepressant indicated for the treatment of major depressive disorder (MDD). It 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, as a partial agonist of the 5-HT1B receptor, an agonist of 5-HT1A, and an antagonist of the 5-HT3, 5-HT1D, and 5-HT7 receptors. SMSs were developed because there are many different subtypes of serotonin receptors, however, not all of these receptors appear to be involved in the antidepressant effects of SRIs. Some serotonin receptors seem to play a relatively neutral or insignificant role in the regulation of mood, but others, such as 5-HT1A autoreceptors and 5-HT7 receptors, appear to play an oppositional role in the efficacy of SRIs in treating depression.

Major Depressive Disorder

Vortioxetine is indicated for the treatment of major depressive disorder (MDD). The efficacy of Vortioxetine was established in six 6 to 8 week studies (including one study in the elderly) and one maintenance study in adults.

Vortioxetine is an antidepressant in a group of drugs called selective serotonin reuptake inhibitors (SSRIs). Vortioxetine affects chemicals in the brain that may become unbalanced.

Vortioxetine is used to treat major depressive disorder in adults.

Vortioxetine may also be used for purposes not listed in this medication guide.

General Instruction for Use

The recommended starting dose is 10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the United States. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses.

Maintenance/Continuation/Extended Treatment

It is generally agreed that acute episodes of major depression should be followed by several months or longer of sustained pharmacologic therapy. A maintenance study of Vortioxetine demonstrated that Vortioxetine decreased the risk of recurrence of depressive episodes compared to placebo.

Discontinuing Treatment

Although Vortioxetine can be abruptly discontinued, in placebo-controlled trials patients experienced transient adverse reactions such as headache and muscle tension following abrupt discontinuation of Vortioxetine 15 mg/day or 20 mg/day. To avoid these adverse reactions, it is recommended that the dose be decreased to 10 mg/day for one week before full discontinuation of Vortioxetine 15 mg/day or 20 mg/day.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with Vortioxetine to avoid the risk of Serotonin Syndrome. Conversely, at least 21 days should be allowed after stopping Vortioxetine before starting an MAOI intended to treat psychiatric disorders.

Use of Vortioxetine with Other MAOIs such as Linezolid or Methylene Blue

Do not start Vortioxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.

In some cases, a patient already receiving Vortioxetine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Vortioxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 21 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Vortioxetine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Vortioxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.

Use of Vortioxetine in Known CYP2D6 Poor Metabolizers or in Patients Taking Strong CYP2D6 Inhibitors

The maximum recommended dose of Vortioxetine is 10 mg/day in known CYP2D6 poor metabolizers. Reduce the dose of Vortioxetine by one-half when patients are receiving a CYP2D6 strong inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) concomitantly. The dose should be increased to the original level when the CYP2D6 inhibitor is discontinued.

Use of Vortioxetine in Patients Taking Strong CYP Inducers

Consider increasing the dose of Vortioxetine when a strong CYP inducer (e.g., rifampin, carbamazepine, or phenytoin) is coadministered for greater than 14 days. The maximum recommended dose should not exceed three times the original dose. The dose of Vortioxetine should be reduced to the original level within 14 days, when the inducer is discontinued.

See also:
What is the most important information I should know about Vortioxetine?

Use Vortioxetine as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Vortioxetine comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Vortioxetine refilled.
• Take Vortioxetine by mouth with or without food.
• Taking Vortioxetine at the same time each day will help you remember to take it.
• Continue to take Vortioxetine even if you feel well. Do not miss any doses.
• Do not suddenly stop taking Vortioxetine without checking with your doctor. You may have an increased risk of side effects (eg, mood swings, dizziness, headache, light-headedness, runny nose, stiff muscles, sudden outburst of anger). If you need to stop Vortioxetine, your doctor may need to gradually lower your dose.
• If you miss a dose of Vortioxetine, take it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.

Ask your health care provider any questions you may have about how to use Vortioxetine.

Use: Labeled Indications

Major depressive disorder: Treatment of major depressive disorder (MDD).

See also:
What other drugs will affect Vortioxetine?

CNS Active Agents

Monoamine Oxidase Inhibitors

Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI.

Serotonergic Drugs

Based on the mechanism of action of Vortioxetine and the potential for serotonin toxicity, serotonin syndrome may occur when Vortioxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if Vortioxetine is co-administered with other serotonergic drugs. Treatment with Vortioxetine and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs.

Other CNS Active Agents

No clinically relevant effect was observed on steady state lithium exposure following coadministration with multiple daily doses of Vortioxetine. Multiple doses of Vortioxetine did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that Vortioxetine (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Details on the potential pharmacokinetic interactions between Vortioxetine and bupropion can be found in Section 7.3.

Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. 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. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin.

Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of Vortioxetine, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin. Coadministration of aspirin 150 mg/day with multiple daily doses of Vortioxetine had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when Vortioxetine is initiated or discontinued.

Potential For Other Drugs To Affect Vortioxetine

Reduce Vortioxetine dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the Vortioxetine dose when a strong CYP inducer (e.g., rifampicin, carbamazepine, phenytoin) is coadministered. The maximum dose is not recommended to exceed three times the original dose (Figure 1).

Figure 1: Impact of Other Drugs on Vortioxetine PK

Potential For Vortioxetine To Affect Other Drugs

No dose adjustment for the comedications is needed when Vortioxetine is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinide), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary.

Vortioxetine and its metabolites are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected.

In addition, Vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of Vortioxetine is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of Vortioxetine with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2).

Because Vortioxetine is highly bound to plasma protein, coadministration of Vortioxetine with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of Vortioxetine (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed.

Figure 2: Impact of Vortioxetine on PK of Other Drugs

Drug Abuse And Dependence

Vortioxetine is not a controlled substance.

See also:
What are the possible side effects of Vortioxetine?

The following adverse reactions are discussed in greater detail in other sections of the label.

• Hypersensitivity
• Clinical Worsening and Suicide Risk
• Serotonin Syndrome
• Abnormal Bleeding
• Activation of Mania/Hypomania
• Hyponatremia

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

Patient Exposure

Vortioxetine was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in pre-marketing clinical studies; 2616 of those patients were exposed to Vortioxetine in 6 to 8 week, placebo-controlled studies at doses ranging from 5 mg to 20 mg once daily and 204 patients were exposed to Vortioxetine in a 24 week to 64 week placebo-controlled maintenance study at doses of 5 mg to 10 mg once daily. Patients from the 6 to 8 week studies continued into 12-month open-label studies. A total of 2586 patients were exposed to at least one dose of Vortioxetine in open-label studies, 1727 were exposed to Vortioxetine for six months and 885 were exposed for at least one year.

Adverse Reactions Reported as Reasons for Discontinuation of Treatment

In pooled 6 to 8 week placebo-controlled studies the incidence of patients who received Vortioxetine 5 mg/day, 10 mg/day, 15 mg/day and 20 mg/day and discontinued treatment because of an adverse reaction was 5%, 6%, 8% and 8%, respectively, compared to 4% of placebo-treated patients. Nausea was the most common adverse reaction reported as a reason for discontinuation.

Common Adverse Reactions in Placebo-Controlled MDD Studies

The most commonly observed adverse reactions in MDD patients treated with Vortioxetine in 6 to 8 week placebo-controlled studies (incidence ≥ 5% and at least twice the rate of placebo) were nausea, constipation and vomiting.

Table 2 shows the incidence of common adverse reactions that occurred in ≥ 2% of MDD patients treated with any Vortioxetine dose and at least 2% more frequently than in placebo-treated patients in the 6 to 8 week placebo-controlled studies.

Table 2: Common Adverse Reactions Occurring in ≥ 2% of Patients Treated with any Vortioxetine Dose and at Least 2% Greater than the Incidence in Placebo-treated Patients

Nausea

Nausea was the most common adverse reaction and its frequency was dose-related (Table 2). It was usually considered mild or moderate in intensity and the median duration was 2 weeks. Nausea was more common in females than males. Nausea most commonly occurred in the first week of Vortioxetine treatment with 15 to 20% of patients experiencing nausea after 1 to 2 days of treatment. Approximately 10% of patients taking Vortioxetine 10 mg/day to 20 mg/day had nausea at the end of the 6 to 8 week placebo-controlled studies.

Sexual Dysfunction

Difficulties in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders, but they may also be consequences of pharmacologic treatment.

In the MDD 6 to 8 week controlled trials of Vortioxetine, voluntarily reported adverse reactions related to sexual dysfunction were captured as individual event terms. These event terms have been aggregated and the overall incidence was as follows. In male patients the overall incidence was 3%, 4%, 4%, 5% in Vortioxetine 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to 2% in placebo. In female patients, the overall incidence was < 1%, 1%, < 1%, 2% in Vortioxetine 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to < 1% in placebo.

Because voluntarily reported adverse sexual reactions are known to be underreported, in part because patients and physicians may be reluctant to discuss them, the Arizona Sexual Experiences Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in seven placebo-controlled trials. The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction.

The presence or absence of sexual dysfunction among patients entering clinical studies was based on their ASEX scores. For patients without sexual dysfunction at baseline (approximately 1/3 of the population across all treatment groups in each study), Table 3 shows the incidence of patients that developed treatment-emergent sexual dysfunction when treated with Vortioxetine or placebo in any fixed dose group. Physicians should routinely inquire about possible sexual side effects.

Table 3: ASEX Incidence of Treatment Emergent Sexual Dysfunction*

Adverse Reactions Following Abrupt Discontinuation of Vortioxetine Treatment

Discontinuation symptoms have been prospectively evaluated in patients taking Vortioxetine 10 mg/day, 15 mg/day, and 20 mg/day using the Discontinuation-Emergent Signs and Symptoms (DESS) scale in clinical trials. Some patients experienced discontinuation symptoms such as headache, muscle tension, mood swings, sudden outbursts of anger, dizziness, and runny nose in the first week of abrupt discontinuation of Vortioxetine 15 mg/day and 20 mg/day.

Laboratory Tests

Vortioxetine 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 Vortioxetine. In the 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Vortioxetine during the initial 12-week, open-label phase, there were no clinically important changes in lab test parameters between Vortioxetine and placebo-treated patients.

Weight

Vortioxetine 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 6-month, double-blind, placebo-controlled phase of a long-term study in patients who had responded to Vortioxetine during the initial 12-week, open-label phase, there was no significant effect on body weight between Vortioxetine and placebo-treated patients.

Vital Signs

Vortioxetine 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

Nervous system disorders — dysgeusia

Vascular disorders — flushing