Side Effects of Trintellix (vortioxetine)

Trintellix (vortioxetine) (formerly known as Brintellix) is an antidepressant used to treat major depressive disorder (MDD).

Trintellix decreases the reuptake of serotonin just like selective serotonin reuptake inhibitors (SSRIs). It also stimulates various serotonin receptors in the brain. The exact mechanism by which Trintellix improves mood in patients with major depressive disorder is not known.

It may have a role in enhancing the activity of the neurotransmitter serotonin in the brain by inhibiting the transport of serotonin. Additionally, Trintellix appears to block or stimulate some serotonin receptors. The exact contribution of the respective activity of Trintellix at these receptor sites requires further investigation.

Common side effects of Trintellix include

• nausea,
• diarrhea,
• dizziness,
• gas (flatulence),
• sexual dysfunction,
• constipation, and
• vomiting.

Serious side effects of Trintellix include

• a rare but life-threatening condition called serotonin syndrome.

Drug interactions of Trintellix include monoamine oxidase inhibitors (MOAIs), certain antidepressants, triptans, tryptophan, tramadol, St. John's wort, amphetamines, methylphenidate, and buspirone, which when combined with Trintellix can cause serotonin syndrome, a rare but serious disorder.

Use of Trintellix may increase the risk of bleeding if taken with warfarin, aspirin, or non-steroidal anti-inflammatory drugs (NSAIDS).

Strong CYP2D6 inhibitors such as bupropion, paroxetine, and quinidine may increase the blood levels of Trintellix, and consequently increase the risk for side effects. Strong CYP2D6 inducers such as rifampin, carbamazepine, and phenytoin may decrease the blood levels of Trintellix resulting in poor treatment outcomes.

Trintellix has not been adequately evaluated in pregnant women. Due to the lack of conclusive safety data, Trintellix should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. It is unknown if Trintellix is excreted in breast milk. Due to the lack of safety data, Trintellix should be used cautiously in females who are breastfeeding.

The most common side effects of vortioxetine treatment are:

• Nausea,
• Diarrhea
• Dizziness
• Flatulence
• Sexual dysfunction
• Constipation
• Vomiting

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
• Angle Closure Glaucoma
• 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

• Trintellix was evaluated for safety in 4746 patients (18 years to 88 years of age) diagnosed with MDD who participated in premarketing clinical studies; 2616 of those patients were exposed to Trintellix in 6 to 8 week, placebo-controlled studies at doses ranging from 5 mg to 20mg once daily and 204 patients were exposed to Trintellix in a 24 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 Trintellix in open-label studies, 1727 were exposed to Trintellix 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 Trintellix 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 Trintellix 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 Trintellix 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 Trintellix 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 two weeks.
• Nausea was more common in females than males. Nausea most commonly occurred in the first week of Trintellix treatment with 15 to 20% of patients experiencing nausea after one to two days of treatment.
• Approximately 10% of patients taking Trintellix 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 addition to the data from the MDD studies mentioned below, Trintellix has been prospectively assessed for its effects in MDD patients with existing TESD induced by prior SSRI treatment and in healthy adults with normal sexual function at baseline.

Voluntarily Reported Adverse Reactions of Sexual Dysfunction

• In the MDD 6 to 8 week controlled trials of Trintellix, 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 Trintellix 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 Trintellix 5 mg/day, 10 mg/day, 15 mg/day, 20 mg/day, respectively, compared to <1% in placebo.

Adverse Reactions of Sexual Dysfunction in Patients with Normal Sexual Functioning at Baseline

• 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 self-reported 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 TESD when treated with Trintellix 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 Trintellix Treatment

• Discontinuation symptoms have been prospectively evaluated in patients taking Trintellix 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 Trintellix 15 mg/day and 20 mg/day.

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. 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

Nervous system disorders: dysgeusia

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.

Metabolic disorders: weight gain

Nervous system disorders: seizure

Skin and subcutaneous tissue disorders: rash, generalized rash

Gastrointestinal System: acute pancreatitis

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 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.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.).

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.

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 0.6 g/kg).

Details on the potential pharmacokinetic interactions between Trintellix 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 Trintellix, 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 Trintellix 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 Trintellix is initiated or discontinued.

Potential For Other Drugs To Affect Trintellix

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

Potential For Trintellix To Affect Other Drugs

No dose adjustment for the comedications is needed when Trintellix is coadministered with a substrate of

• CYP1A2 (e.g., duloxetine, caffeine),
• CYP2A6, CYP2B6 (e.g., bupropion),
• CYP2C8 (e.g., repaglinide),
• CYP2C9 (e.g., S-warfarin, tolbutamide),
• CYP2C19 (e.g., diazepam),
• CYP2D6 (e.g., venlafaxine, dextromethorphan),
• CYP3A4/5 (e.g., budesonide, midazolam),
• P-gp (e.g., digoxin),
• BCRP (e.g., methotrexate),
• OATP1B1/3 (e.g., rosuvastatin) and
• OCT2 (e.g., metformin).

In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary.

Vortioxetine and its metabolite(s) 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,
• P-gp,
• BCRP,
• BSEP,
• MATE1,
• MATE2-K,
• OAT1,
• OAT3,
• OATP1B1,
• OATP1B3,
• OCT1 and
• OCT2.

As such, no clinically relevant interactions with drugs metabolized/transported by these CYP enzymes or transporters 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 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.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 Trintellix with another drug that is highly protein bound may increase free concentrations of the other drug.

However, in a clinical study with coadministration of Trintellix (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed.

Drug Abuse And Dependence

Trintellix is not a controlled substance.